Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Neurohormonal activation in heart failure with reduced ejection fraction

Key Points

  • Heart failure with reduced ejection fraction (HFrEF) is initiated when an 'index event' causes the pumping capacity of the heart to be impaired

  • Reduced pumping capacity of the heart results in compensatory activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system, which together is referred to as 'neurohormonal activation'

  • Neurohormonal activation results in a series of coordinated responses that collectively work to restore cardiovascular homeostasis in the short term

  • Sustained neurohormonal activation drives the progression of HFrEF through the deleterious effects exerted on the circulation and the myocardium

  • Antagonism of neurohormonal systems forms the basis of modern therapy for HFrEF

Abstract

Heart failure with reduced ejection fraction (HFrEF) develops when cardiac output falls as a result of cardiac injury. The most well-recognized of the compensatory homeostatic responses to a fall in cardiac output are activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS). In the short term, these 'neurohormonal' systems induce a number of changes in the heart, kidneys, and vasculature that are designed to maintain cardiovascular homeostasis. However, with chronic activation, these responses result in haemodynamic stress and exert deleterious effects on the heart and the circulation. Neurohormonal activation is now known to be one of the most important mechanisms underlying the progression of heart failure, and therapeutic antagonism of neurohormonal systems has become the cornerstone of contemporary pharmacotherapy for heart failure. In this Review, we discuss the effects of neurohormonal activation in HFrEF and highlight the mechanisms by which these systems contribute to disease progression.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Activation of neurohormonal systems in heart failure.
Figure 2: Effects of sympathetic nervous system activation.
Figure 3: Cardiac and cellular remodelling in response to haemodynamic overloading.

References

  1. 1

    Mann, D. L. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ. Res. 116, 1254–1268 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Rouleau, J. L. et al. Activation of neurohumoral systems following acute myocardial infarction. Am. J. Cardiol. 68, 80D–86D (1991).

    Article  CAS  PubMed  Google Scholar 

  3. 3

    Packer, M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J. Am. Coll. Cardiol. 20, 248–254 (1992).

    Article  CAS  PubMed  Google Scholar 

  4. 4

    Piepoli, M. et al. Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure: effects of physical training. Circulation 93, 940–952 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. 5

    Giannoni, A. et al. Combined increased chemosensitivity to hypoxia and hypercapnia as a prognosticator in heart failure. J. Am. Coll. Cardiol. 53, 1975–1980 (2009).

    Article  PubMed  Google Scholar 

  6. 6

    Ponikowski, P. P. et al. Muscle ergoreceptor overactivity reflects deterioration in clinical status and cardiorespiratory reflex control in chronic heart failure. Circulation 104, 2324–2330 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. 7

    Floras, J. S. & Ponikowski, P. The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction. Eur. Heart J. 36, 1974–1982 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Florea, V. G. & Cohn, J. N. The autonomic nervous system and heart failure. Circ. Res. 114, 1815–1826 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Sigurdsson, A. & Swedberg, K. The role of neurohormonal activation in chronic heart failure and postmyocardial infarction. Am. Heart J. 132, 229–234 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. 10

    Cohn, J. N. et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N. Engl. J. Med. 311, 819–823 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Dzau, V. J., Colucci, W. S., Hollenberg, N. K. & Williams, G. H. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation 63, 645–651 (1981).

    Article  CAS  PubMed  Google Scholar 

  12. 12

    Francis, G. S. et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. Circulation 82, 1724–1729 (1990).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    Mann, D. L., Kent, R. L., Parsons, B. & Cooper, G. I. V. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 85, 790–804 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Adams, J. W. et al. Enhanced Gαq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc. Natl Acad. Sci. USA 95, 10140–10145 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Bisognano, J. D. et al. Myocardial-directed overexpression of the human beta(1)-adrenergic receptor in transgenic mice. J. Mol. Cell Cardiol. 32, 817–830 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Engelhardt, S., Hein, L., Wiesmann, F. & Lohse, M. J. Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice. Proc. Natl Acad. Sci. USA 96, 7059–7064 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Bozkurt, B. et al. Pathophysiologically relevant concentrations of tumor necrosis factor-α promote progressive left ventricular dysfunction and remodeling in rats. Circulation 97, 1382–1391 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. 18

    Teerlink, J. R., Pfeffer, J. M. & Pfeffer, M. A. Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats. Circ. Res. 75, 105–113 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. 19

    Cohn, J. N. et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N. Engl. J. Med. 325, 303–310 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Packer, M. et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N. Engl. J. Med. 334, 1350–1355 (1996).

    Article  Google Scholar 

  21. 21

    Pitt, B. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N. Engl. J. Med. 341, 709–717 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N. Engl. J. Med. 325, 293 (1991).

  23. 23

    MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353, 2001–2007 (1999).

  24. 24

    Bristow, M. R. et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 94, 2807–2816 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. 25

    Yancy, C. W. 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. 15, e147–e239 (2013).

    Article  Google Scholar 

  26. 26

    Notarius, C. F., Millar, P. J. & Floras, J. S. Muscle sympathetic activity in resting and exercising humans with and without heart failure. Appl. Physiol. Nutr. Metab. 40, 1107–1115 (2015).

    Article  PubMed  Google Scholar 

  27. 27

    Weinberger, M. H., Aoi, W. & Henry, D. P. Direct effect of beta-adrenergic stimulation on renin release by the rat kidney slice in vitro. Circ. Res. 37, 318–324 (1975).

    Article  CAS  PubMed  Google Scholar 

  28. 28

    Bekheirnia, M. R. & Schrier, R. W. Pathophysiology of water and sodium retention: edematous states with normal kidney function. Curr. Opin. Pharmacol. 6, 202–207 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    McCollum, L. T., Gallagher, P. E. & Ann Tallant, E. Angiotensin-(1–7) attenuates angiotensin II-induced cardiac remodeling associated with upregulation of dual-specificity phosphatase 1. Am. J. Physiol. Heart Circ. Physiol. 302, H801–H810 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Wamberg, C., Plovsing, R. R., Sandgaard, N. C. & Bie, P. Effects of different angiotensins during acute, double blockade of the renin system in conscious dogs. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R971–980 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. 31

    Huang, B. S. et al. Inhibition of brain angiotensin III attenuates sympathetic hyperactivity and cardiac dysfunction in rats post-myocardial infarction. Cardiovasc. Res. 97, 424–431 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. 32

    Esteban, V. et al. Angiotensin IV activates the nuclear transcription factor-kappaB and related proinflammatory genes in vascular smooth muscle cells. Circ. Res. 96, 965–973 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. 33

    Bomback, A. S. & Klemmer, P. J. The incidence and implications of aldosterone breakthrough. Nat. Clin. Pract. Nephrol. 3, 486–492 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Schrier, R. W. Aldosterone 'escape' versus 'breakthrough'. Nat. Rev. Nephrol. 6, 61 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Pitt, B., Remme, W. & Zannad, F. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 348, 1309–1321 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Braunwald, E. The path to an angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure. J. Am. Coll. Cardiol. 65, 1029–1041 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Schrier, R. W. & Abraham, W. T. Hormones and hemodynamics in heart failure. N. Engl. J. Med. 341, 577–585 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Clerico, A., Recchia, F. A., Passino, C. & Emdin, M. Cardiac endocrine function is an essential component of the homeostatic regulation network: physiological and clinical implications. Am. J. Physiol. Heart Circ. Physiol. 290, H17–H29 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. 39

    Volpe, M., Carnovali, M. & Mastromarino, V. The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin. Sci. (Lond.) 130, 57–77 (2016).

    Article  CAS  Google Scholar 

  40. 40

    McMurray, J. J. et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 317, 993–1004 (2014).

    Article  CAS  Google Scholar 

  41. 41

    Shah, A. M. & Mann, D. L. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet 378, 704–712 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Mann, D. L. & Bristow, M. R. Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation 111, 2837–2849 (2005).

    Article  PubMed  Google Scholar 

  43. 43

    Toischer, K. et al. Differential cardiac remodeling in preload versus afterload. Circulation 122, 993–1003 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    van Berlo, J. H., Maillet, M. & Molkentin, J. D. Signaling effectors underlying pathologic growth and remodeling of the heart. J. Clin. Invest. 123, 37–45 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Lowes, B. D. et al. Changes in gene expression in the intact human heart. Downregulation of alpha-Myosin heavy chain in hypertrophied, failing ventricular myocardium. J. Clin. Invest. 100, 2315–2324 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Kostin, S., Hein, S., Arnon, E., Scholz, D. & Schaper, J. The cytoskeleton and related proteins in the human failing heart. Heart Fail. Rev. 5, 271–280 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Hein, S., Kostin, S., Heling, A., Maeno, Y. & Schaper, J. The role of the cytoskeleton in heart failure. Cardiovasc. Res. 45, 273–278 (2000).

    CAS  Google Scholar 

  48. 48

    Rockman, H. A., Koch, W. J. & Lefkowitz, R. J. Seven-transmembrane-spanning receptors and heart function. Nature 415, 206–212 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Lymperopoulos, A., Rengo, G. & Koch, W. J. Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ. Res. 113, 739–753 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Feldman, D. S., Carnes, C. A., Abraham, W. T. & Bristow, M. R. Mechanisms of disease: beta-adrenergic receptors—alterations in signal transduction and pharmacogenomics in heart failure. Nat. Clin. Pract. Cardiovasc. Med. 2, 475–483 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Port, J. D. & Bristow, M. R. Altered beta-adrenergic receptor gene regulation and signaling in chronic heart failure. J. Mol. Cell Cardiol. 33, 887–905 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Bristow, M. R. et al. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N. Engl. J. Med. 307, 205–211 (1982).

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Bristow, M. R. et al. Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ. Res. 59, 297–309 (1986).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Reiter, E. & Lefkowitz, R. J. GRKs and beta-arrestins: roles in receptor silencing, trafficking and signaling. Trends Endocrinol. Metab. 17, 159–165 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. 55

    Ungerer, M., Bohm, M., Elce, J. S., Erdmann, E. & Lohse, M. J. Altered expression of beta-adrenergic receptor kinase and beta1-adrenergic receptors in the failing human heart. Circulation 87, 454–463 (1993).

    Article  CAS  PubMed  Google Scholar 

  56. 56

    Iaccarino, G., Tomhave, E. D., Lefkowitz, R. J. & Koch, W. J. Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade. Circulation 98, 1783–1789 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. 57

    Rockman, H. A. et al. Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc. Natl Acad. Sci. USA 95, 7000–7005 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Rengo, G. et al. Myocardial adeno-associated virus serotype 6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation 119, 89–98 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. 59

    Raake, P. W. et al. AAV6.betaARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model. Eur. Heart J. 34, 1437–1447 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. 60

    Harding, V. B., Jones, L. R., Lefkowitz, R. J., Koch, W. J. & Rockman, H. A. Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure. Proc. Natl Acad. Sci. USA 98, 5809–5814 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Rajabi, M., Kassiotis, C., Razeghi, P. & Taegtmeyer, H. Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev. 12, 331–343 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    Lowes, B. D. et al. Myocardial gene expression in dilated cardiomyopathy treated with beta- blocking agents. N. Engl. J. Med. 346, 1357–1365 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. 63

    Brooks, W. W. et al. Captopril modifies gene expression in hypertrophied and failing hearts of aged spontaneously hypertensive rats. Hypertension 30, 1362–1368 (1997).

    Article  CAS  Google Scholar 

  64. 64

    Wang, J., Guo, X. & Dhalla, N. S. Modification of myosin protein and gene expression in failing hearts due to myocardial infarction by enalapril or losartan. Biochim. Biophys. Acta 1690, 177–184 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Marks, A. R. Calcium cycling proteins and heart failure: mechanisms and therapeutics. J. Clin. Invest. 123, 46–52 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Marx, S. O. et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101, 365–376 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. 67

    Arai, M., Alpert, N. R., MacLennan, D. H., Barton, P. & Periasamy, M. Alterations in sarcoplasmic reticulum gene expression in human heart failure. Circ. Res. 72, 463–469 (1993).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Hasenfuss, G. et al. Relation between myocardial function and expression of sarcoplasmic reticulum ca2+-ATPase in failing and nonfailing human myocardium. Circ. Res. 75, 434–442 (1994).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Reiken, S. et al. Beta-adrenergic receptor blockers restore cardiac calcium release channel (ryanodine receptor) structure and function in heart failure. Circulation 104, 2843–2848 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. 70

    Reiken, S. et al. Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure. Circulation 107, 2459–2466 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Mann, D. L. Left ventricular size and shape: determinants of mechanical signal transduction pathways. Heart Fail. Rev. 10, 95–100 (2005).

    Article  PubMed  Google Scholar 

  72. 72

    Guerra, S. et al. Myocyte death in the failing human heart is gender dependent. Circ. Res. 85, 856–866 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Kostin, S. et al. Myocytes die by multiple mechanisms in failing human hearts. Circ. Res. 92, 715–724 (2003).

    Article  CAS  Google Scholar 

  74. 74

    Whelan, R. S., Kaplinskiy, V. & Kitsis, R. N. Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu. Rev. Physiol. 72, 19–44 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. 75

    Kroemer, G. et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 16, 3–11 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Tan, L. B., Jalil, J. E., Pick, R., Janicki, J. S. & Weber, K. T. Cardiac myocyte necrosis induced by angiotensin II. Circ. Res. 69, 1185–1195 (1991).

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Todd, G. L., Baroldi, G., Pieper, G. M., Clayton, F. C. & Eliot, R. S. Experimental catecholamine-induced myocardial ncrosis I. Morphology, quantification and regional distribution of acute contraction band lesions. J. Mol. Cell. Cardiol. 17, 317–338 (1985).

    Article  CAS  PubMed  Google Scholar 

  78. 78

    Zhang, W. et al. Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. J. Am. Heart Assoc. 4, e001993 (2015).

    PubMed  PubMed Central  Google Scholar 

  79. 79

    Epelman, S., Liu, P. P. & Mann, D. L. Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat. Rev. Immunol. 15, 117–129 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Olivetti, G. et al. Apoptosis in the failing human heart. N. Engl. J. Med. 336, 1131–1141 (1997).

    Article  CAS  PubMed  Google Scholar 

  81. 81

    Saraste, A. et al. Cardiomyocyte apoptosis and progression of heart failure to transplantation. Eur. J. Clin. Invest. 29, 380–386 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Wencker, D. et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J. Clin. Invest. 111, 1497–1504 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Communal, C., Singh, K., Sawyer, D. B. & Colucci, W. S. Opposing effects of beta(1)- and beta(2)-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein. Circulation 100, 2210–2212 (1999).

    Article  CAS  PubMed  Google Scholar 

  84. 84

    Haudek, S. B., Taffet, G. E., Schneider, M. D. & Mann, D. L. TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways. J. Clin. Invest. 117, 2692–2701 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Kajstura, J. et al. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J. Mol. Cell Cardiol. 29, 859–870 (1997).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Kroemer, G., Marino, G. & Levine, B. Autophagy and the integrated stress response. Mol. Cell 40, 280–293 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Lavandero, S., Chiong, M., Rothermel, B. A. & Hill, J. A. Autophagy in cardiovascular biology. J. Clin. Invest. 125, 55–64 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Ma, X. et al. Impaired autophagosome clearance contributes to cardiomyocyte death in ischemia/reperfusion injury. Circulation 125, 3170–3181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Kong, P., Christia, P. & Frangogiannis, N. G. The pathogenesis of cardiac fibrosis. Cell. Mol. Life Sci. 71, 549–574 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Davis, J. & Molkentin, J. D. Myofibroblasts: trust your heart and let fate decide. J. Mol. Cell Cardiol. 70, 9–18 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Hartupee, J. & Mann, D. L. Role of inflammatory cells in fibroblast activation. J. Mol. Cell Cardiol 93, 143–148 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Schorb, W. et al. Angiotensin II is mitogenic in neonatal rat cardiac fibroblasts. Circ. Res. 72, 1245–1254 (1993).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Sadoshima, J. I. & Izumo, S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ. Res. 73, 413–423 (1993).

    Article  CAS  PubMed  Google Scholar 

  94. 94

    Brilla, C. G., Funck, R. C. & Rupp, H. Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation 102, 1388–1393 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. 95

    Izawa, H. et al. Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: a pilot study. Circulation 112, 2940–2945 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Zannad, F., Alla, F., Dousset, B., Perez, A. & Pitt, B. 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). Rales Investigators. Circulation 102, 2700–2706 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. 97

    Li, Y. Y., Feldman, A. M., Sun, Y. & McTiernan, C. F. Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation 98, 1728–1734 (1998).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Creemers, E. E. et al. Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice. Am. J. Physiol. Heart Circ. Physiol. 284, H364–H371 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Ducharme, A. et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J. Clin. Invest. 106, 55–62 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Kim, H. E. et al. Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. J. Clin. Invest. 106, 857–866 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Peterson, J. T. et al. Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation 103, 2303–2309 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. 102

    Koitabashi, N. & Kass, D. A. Reverse remodeling in heart failure—mechanisms and therapeutic opportunities. Nat. Rev. Cardiol. 9, 147–157 (2012).

    Article  CAS  Google Scholar 

  103. 103

    Mann, D. L., Barger, P. M. & Burkhoff, D. Myocardial recovery: myth, magic or molecular target? J. Am. Coll. Cardiol. 60, 2465–2472 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors' research is supported by research funds from the NIH (R01 HL58081, RO1 111094, T32 HL007081).

Author information

Affiliations

Authors

Contributions

Both authors researched data for the article, discussed its content, wrote the manuscript, and reviewed/edited it before submission.

Corresponding author

Correspondence to Douglas L. Mann.

Ethics declarations

Competing interests

D.L.M. is a consultant to Novartis and is on the steering committee for the PARADISE trial. J.H. declares no competing interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hartupee, J., Mann, D. Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol 14, 30–38 (2017). https://doi.org/10.1038/nrcardio.2016.163

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing