HFrEF Learning Center

Reduced cardiac contractility is central to heart failure with reduced ejection fraction (HFrEF) manifestation and progression

References

  1. Kemp CD, et al. Cardiovasc Pathol. 2012;21:365-371.
  2. Piano MR, et al. Heart Lung. 1998;27:3-19.
  3. Hasenfuss G, et al. Pathophysiology of heart failure. Zipes DP, et al, eds. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 11th ed. Philadelphia, PA: Elsevier Inc; 2019;442-461.
  4. Opie L, et al. Mechanisms of cardiac contraction and relaxation. In: Mann DL, et al, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: Elsevier Inc. 2012.
  5. Kuo IY, et al. Cold Spring Harb Perspect Biol. 2015;7:a006023. doi:10.1101/cshperspect.a006023
  6. Neubauer S. N Engl J Med. 2007;356:1140-1151.
  7. Wijayasiri L, et al. Cardiac contractility. In: Vincent JL, Hall JB, eds. Encyclopedia of Intensive Care Medicine. Berlin, Germany: Springer-Verlag Berlin Heidelberg. 2012;460-462.
  8. Psotka MA, et al. J Am Coll Cardiol. 2019;73:2345-2353.
  9. Solaro RJ. Pressure volume loops provide a quantification of contractility. In: Regulation of Cardiac Contractility. San Rafael, CA: Morgan & Claypool Life Sciences; 2011.
  10. Chengode S. Ann Card Anaesth. 2016;19(suppl):S26-S34.
  11. Biering-Sørensen T, et al. Eur J Heart Fail. 2018;20:1106-1114.
  12. Kolev N, et al. Anesth Analg. 1995;81:889-890.
  13. Solomon SD, et al. Circulation. 2005;112:3738-3744.
  14. Kolias TJ, et al. J Am Coll Cardiol. 2000;36:1594-1599.
  15. Cikes M, et al. Eur Heart J. 2016;37:1642-1650.
  16. Sheth PJ, et al. Radiographics. 2015;35:1335-1351.
  17. Meric M, et al. Int J Cardiovasc Imaging. 2014;30:1057-1064.
  18. Reant P, et al. Eur J Echocardiogr. 2010;11:834-844.
  19. Haiden A, et al. Am J Hypertens. 2014;27:702-709.
  20. Katz AM, et al. Euro Heart J. 2016;37:449-454.
  21. Mann DL, et al. Heart failure and cor pulmonale. In: Longo DL, et al, eds. Harrison’s Internal Medicine. 18th ed. New York, NY: McGraw Hill; 2012:1901-1915.
  22. Arrigo M, et al. Eur Heart J Suppl. 2016;18(suppl G):G11-G18.
  23. Klabunde RE, et al. Cellular structure and function. In: Klabunde RE, et al, ed. Cardiovascular Physiology Concepts. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins/Wolters Kluwer; 2012;41-59.
  24. MacLeod KT. F1000Research. 2016;5:1770. doi:10.12688/f1000research.8661.1. eCollection 2016.
  25. Bers DM, et al. Mechanisms of cardiac contraction and relaxation. In: Zipes DP, et al, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 11th ed. Philadelphia, PA: Elsevier Inc. 2019:418-441.
  26. deGoma EM, et al. J Am Coll Cardiol. 2006;48:2397-2409.
  27. Kass DA, et al. Circulation. 2006;113:305-315.
  28. Martínez MS, et al. Vessel Plus. 2017;1:230-241.
  29. Wang J, et al. J Zhejiang Univ Sci B (Biomed & Biotechnol). 2013;14:688-695.
  30. Teerlink JR. Heart Fail Rev. 2009;14:289-298.
  31. Yancy CW, et al; Writing Committee Members. Circulation. 2013;128:e240-e327.
  32. Spudich JA. Biophys J. 2014;106:1236-1249.
  33. Planelles-Herrero VJ, et al. Nat Commun. 2017;8:190. doi:10.1038/s41467-017-00176-5
  34. Moss RL, et al. Circ Res. 2004;94:1290-1300.
  35. Zhou B, et al. J Clin Invest. 2018;128:3716-3726.
  36. Houser SR, et al. Circ Res. 2003;92:350-358.
  37. Luo M, et al. Circ Res. 2013;113:690-708.
  38. Jozwiak M, et al. Semin Respir Crit Care Med. 2011;32:206-214.
  39. Malik FI, et al. J Mol Cell Cardiol. 2011;51:454-461.
  40. Francis GS, et al. J Am Coll Cardiol. 2014;63:2069-2078.
  41. Ferrari R, et al. Euro Heart J Suppl. 2016 (suppl G);G3-G10.
  42. Atherton JJ. Scientifica (Cairo). 2012;2012:279731. doi:10.6064/2012/279731
  43. Kato T, et al. World J Cardiol. 2014;6:1175-1191.
  44. Choi HM, et al. Korean J Intern Med. 2019;34:11-43.

Disruption of contractility is at the core of dysfunction in HFrEF.1

Heart muscle function is dependent on the key contractile proteins of the sarcomere: actin and myosin.5,8
Click here to learn more about actin-myosin interaction.

Contractility drives performance, and the actin-myosin interaction drives contractility.5,8

The sarcomere is the basic contractile unit of the myocyte. Cardiac sarcomeres consist of long, fibrous proteins that form a thick filament made of the contractile protein myosin, and a thin filament made of actin.23 Directly affecting the contractile proteins of the myocardium is referred to as myotropy.8

Myosin acts as a molecular motor that converts energy stored as adenosine triphosphate (ATP) into a contractile force.8

Myosin heads that productively attach to actin filament and produce force contribute to myocyte contraction. Troponin and tropomyosin are associated with the actin filament and regulate the actin-myosin interaction.5,8,23

Intracellular Ca2+ shifts facilitate the actin-myosin interaction via troponin and tropomyosin.5,8,23

Cardiac contraction is executed through the "sliding" of actin and myosin past each other.5,23

This movement is dependent on Ca2+ fluxes and energy production (ATP).5,8,23

The actin-myosin interaction is also ATP dependent.5,8,23

Production of a forceful power stroke:8,26

  1. Myosin catabolizes ATP hydrolysis to become adenosine diphosphate (ADP) + orthophosphate (Pi), and flexion or cocking of the myosin head occurs (weak interaction with actin)
  2. Pi released high-affinity actin-myosin interaction
  3. ADP is released, and extension of myosin head is initiated
  4. Power stroke is completed (moves actin ~ 10 nm)
  5. ATP binds to myosin; myosin dissociates from actin filament

The substantial ATP quantity used for ventricular systole is provided by the mitochondria of the cardiac myocytes. This process is again upregulated by increased Ca2+ concentrations, among other stimuli, including elevated intracellular ADP.8

Ca2+, ATP, troponin, and tropomyocin together drive the actin-myosin interaction, which is the bedrock of myocardial contractility.5,8,23 Converting a greater number of actin-myosin interactions into effective power strokes results in greater contractility.34

Energy production and use within the cell, including ATP, are required for contraction, as well as system reset.6,8

Failing hearts undergo pathologic remodeling, producing inefficiencies that increase demand of ATP while decreasing capacity for ATP.6,35

The cycling of Ca2+ governs exposure of the actin-binding site for myosin attachment.8

There is Ca2+ dysregulation in the failing heart.36,37

Cardiac calcitropy, also known as "traditional inotropy," results in myocardial force augmentation by increasing intracellular Ca2+ concentration.8,38

Ca2+ is toxic at high levels in the myocardium. Elevated Ca2+ increases energy utilization and myocardial oxygen demand, as well as arrhythmogenicity, which can lead to increased morbidity and mortality.39,40

Despite many currently available therapies, further work is needed to improve patient outcomes in HFrEF.

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