ROLE OF SUSTAINED SYMPATHETIC OVERACTIVATION IN THE DEVELOPMENT OF STRUCTURAL AND FUNCTIONAL MYOCARDIAL CHANGES IN HEART FAILURE

Heart failure is associated with profound sympathetic overactivation, which initially develops as an adaptive effect that supports cardiac contractile function. Nevertheless, in the long term, sympathetic activation promotes detrimental myocardial changes, and therefore contributes to systolic dysfunction and poor clinical prognosis. The current knowledge about the mechanisms of these maladaptive effects largely stems from the animal studies that utilized a model of heart failure induced by chronic administration of adrenergic agonists. In this model, sustained adrenergic overactivation was found to induce cardiac hypertrophy owing to the increased protein synthesis in cardiac myocytes, and to promote myocardial fibrosis by stimulating collagen production in cardiac fibroblasts. Catecholamines also produce toxic effects leading to the myocyte cell death via necrosis and apoptosis. Systolic dysfunction in the setting of adrenergic overactivation is partly attributed to the eccentric ventricular chamber remodeling, an effect related to the increased activity of matrix metalloproteinases which digest cross-linked collagen, and promote myocyte slippage. At the cellular level, cardiac contractile failure is linked to the impaired calcium handling. Beta-adreneregic stimulation causes hyperphosphorylation of the ryanodine receptor (RyR2) via cAMP-protein kinase A-dependent mechanism, which increases RyR2 open probability, and hence contributes to the calcium leakage, resulting in depleted sarcoplasmic reticulum calcium stores. This change is further exacerbated owing to the decreased SERCA2a expression in failing cardiac myocytes, which impairs sarcoplasmic reticulum calcium uptake in diastole. Overall, myocardial structural changes upon sustained adrenergic overactivation are related to the increased activity of the renin-angiotensin-aldosterone system, stimulation of the myocardial growth factors, and increased expression of cytokines. The adrenergic cellular growth-promoting effects are mediated through the mitogen-activated protein kinase signaling pathway, transient up-regulation of the immediate-early genes, and activation of transcription factors. These effects translate to the increased synthesis of contractile proteins and their assembly into the organized sarcomeric units in cardiac myocytes.

1. Greenwood J.P., Scott E.M., Stoker J.B., Mary D.A. Hypertensive left ventricular hypertrophy: relation to peripheral sympathetic drive. J Am Coll Cardiol. 2001; 38(6): 1711-1717.

2. Cohn J.N., Levine T.B., Olivari M.T., Garberg V., Lura D., Francis G.S., Simon A.B., Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984; 311(13): 819-823.

3. Kaye D.M., Lefkovits J., Jennings G.L., Bergin P., Broughton A., Esler M.D. Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol. 1995; 26(5): 1257-1263.

4. Osadchii O.E. Cardiac hypertrophy induced by sustained beta-adrenoreceptor activation: pathophysiological aspects. Heart Fail Rev. 2007; 12(1): 66-86.

5. Nichtova Z., Novotova M., Kralova E., Stankovicova T. Morphological and functional characteristics of models of experimental myocardial injury induced by isoproterenol. Gen Physiol Biophys. 2012; 31(2): 141-151.

6. Rona G. Catecholamine cardiotoxicity. J Mol Cell Cardiol. 1985; 17(4): 291-306.

7. Teerlink J.R., Pfeffer J.M., Pfeffer M.A. Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats. Circ Res. 1994; 75(1): 105-113.

8. Schafer M., Frischkopf K., Taimor G., Piper H.M, Schlüter K.D. Hypertrophic effect of selective beta-adrenoceptor stimulation on ventricular cardiomyocytes from adult rat. Am J Physiol. 2000; 279(2): С495-С503.

9. Simpson P., McGrath A., Savion S. Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ Res. 1982; 51(6): 787-801.

10. Barth W., Deten A., Bauer M., Reinohs M., Leicht M., Zimmer H.G. Differential remodeling of the left and right heart after norepinephrine treatment in rats: studies on cytokines and collagen. J Mol Cel Cardiol. 2000; 32(2): 273-284.

11. Deshaies Y., Willemot J., Leblanc J. Protein synthesis, amino acid uptake, and pools during isoproterenol-induced hypertrophy of the rat heart and tibialis muscle. Can J Physiol Pharm. 1981; 59(2): 113-121.

12. Marcus M.L., Koyanagi S., Harrison D.G., Doty D.B., Hiratzka L.F., Eastham C.L. Abnormalities in the coronary circulation that occur as a consequence of cardiac hypertrophy. Am J Med. 1983; 75(3A): 62-66.

13. Weiner M.M., Reich D.L., Lin H.M., Krol M., Fischer G.W. Increased left ventricular myocardial mass is associated with arrhythmias after cardiac surgery. J Cardiothorac Vasc Anesth. 2013; 27(2): 292-297.

14. Bhambi B., Eghbali M. Effect of norepinephrine on myocardial collagen gene expression and response of cardiac fibroblasts after norepinephrine treatment. Am J Pathol. 1991; 139(5): 11311142.

15. Jalil J.E., Doering C.W., Janicki J.S., Pick R., Shroff S.G., Weber K.T. Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res. 1989; 64(6): 1041-1050.

16. Wang J., Song Y., Li H., Shen Q., Shen J., An X., Wu J., Zhang J., Wu Y., Xiao H., Zhang Y. Exacerbated cardiac fibrosis induced by β-adrenergic activation in old mice due to decreased AMPK activity. Clin Exp Pharmacol Physiol. 2016; 43(11): 10291037.

17. Jalil J.E., Janicki J.S., Pick R., Abrahams C, Weber KT. Fibrosis-induced reduction of endomyocardium in the rat after isoproterenol treatment. Circ Res. 1989; 65(2): 258-264.

18. Nguyen T.P., Qu Z., Weiss J.N. Cardiac fibrosis and arrhythmogenesis: the road to repair is paved with perils. J Mol Cell Cardiol. 2014; 70: 83-91.

19. Weber KT. Fibrosis and hypertensive heart disease. Curr Opin Cardiol. 2000; 15(4): 264-272.

20. Goldspink D.F., Burniston J.G., Tan L.B. Cardiomyocyte death and the ageing and failing heart. Exp Physiol. 2003; 88(3): 447-458.

21. Singh K., Xiao L., Remondino A., Sawyer D.B., Colucci W.S. Adrenergic regulation of cardiac myocyte apoptosis. J Cell Physiol. 2001; 189(3): 257-265.

22. Mann D.L., Kent R.L., Parsons B., Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992; 85(2): 790-804.

23. Ellison G.M., Torella D., Karakikes I., Purushothaman S., Curcio A., Gasparri C., Indolfi C., Cable N.T., Goldspink D.F., Nadal-Ginard B. Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells. J Biol Chem. 2007; 282(15): 1139711409.

24. Remondino A., Kwon S.H., Communal C., Pimentel D.R., Sawyer D.B., Singh K., Colucci W.S. Beta- adrenergic receptorstimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway. Circ Res. 2003; 92(2): 136-138.

25. Jiang S., Huo D., Wang X., Zhao H., Tan J., Zeng Q., OʼRourke S.T., Sun C. β-adrenergic receptor-stimulated cardiac myocyte apoptosis: role of cytochrome P450 ω-hydroxylase. J Cardiovasc Pharmacol. 2017; 70(2): 94-101.

26. Grossman W., Jones D., McLaurin L.P. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest. 1975; 56(1): 56-64.

27. Stewart J.M., Patel M.B., Wang J., Ochoa M., Gewitz M., Loud A.V., Anversa P., Hintze T.H. Chronic elevation of norepinephrine in conscious dogs produces hypertrophy with no loss of LV reserve. Am J Physiol. 1992; 262(2): H331-H339.

28. Tang L., Gao W., Taylor P.B. Force-frequency response in isoproterenol-induced hypertrophied rat heart. Eur J Pharmacol. 1996; 318(2-3): 349-356.

29. Mészáros J., Ryder K.O., Hart G. Transient outward current in catecholamine-induced cardiac hypertrophy in the rat. Am J Physiol. 1996: 271(6): H2360-H2367.

30. Baek M., Weiss M. Down-regulation of Na+ pump alpha 2 isoform in isoprenaline-induced cardiac hypertrophy in rat: evidence for increased receptor binding affinity but reduced inotropic potency of digoxin. J Pharmacol Exp Ther. 2005: 313(2): 731-739.

31. Nakajima-Takenaka C., Zhang G.X., Obata K., Tohne K., Matsuyoshi H., Nagai Y., Nishiyama A., Takaki M. Left ventricular function of isoproterenol-induced hypertrophied rat hearts perfused with blood: mechanical work and energetics. Am J Physiol Heart Circ Physiol. 2009; 297(5): H1736- H1743.

32. Chorvatova A., Hart G., Hussain M. Na+/Ca2+ exchange current (INa/Ca) and sarcoplasmic reticulum Ca2+ release in catecholamine-induced cardiac hypertrophy. Cardiovasc Res. 2004; 61(2): 278-287.

33. Siwik D.A., Kuster G.M., Brahmbhatt J.V., Zaidi Z., Malik J., Ooi H., Ghorayeb G. EMMPRIN mediates beta adrenergic receptor-stimulated matrix metalloproteinase activity in cardiac myocytes. J Mol Cell Cardiol. 2008; 44(1): 210-217.

34. Veliotes D.G., Norton G.R., Correia R.J., Strijdom H., Badenhorst D., Brooksbank R., Woodiwiss A.J. Impact of aldosterone receptor blockade on the deleterious cardiac effects of adrenergic activation in hypertensive rats. J Cardiovasc Pharmacol. 2010; 56(2): 203-211.

35. Mueller R.A., Axelrod J. Abnormal cardiac norepinephrine storage in isoproterenol-treated rats. Circ Res. 1968; 23(6): 771778.

36. Marks A.R. Calcium cycling proteins and heart failure: mechanisms and therapeutics. J Clin Invest. 2013; 123(1): 46-52.

37. Mitsuyama S., Takeshita D., Obata K., Zhang G.X., Takaki M. Left ventricular mechanical and energetic changes in long-term isoproterenol-induced hypertrophied hearts of SERCA2a transgenic rats. J Mol Cell Cardiol 2013; 59: 95-106.

38. Grimm D., Elsner D., Schunkert H., Pfeifer M., Griese D., Bruckschlegel G., Muders F., Riegger G.A., Kromer E.P. Development of heart failure following isoproterenol administration in the rat: role of the renin-angiotensin system. Cardiovasc Res. 1998; 37(1): 91-100.

39. Nagano M., Higaki J., Nakamura F., Higashimori K., Nagano N., Mikami H., Ogihara T. Role of cardiac angiotensin II in isoproterenol-induced left ventricular hypertrophy. Hypertension. 1992; 19(6): 708-712.

40. Grimm D., Holmer S.R., Riegger G.A.J., Kromer E.P. Effects of beta-receptor blockade and angiotensin II type I receptor antagonism in isoproterenol-induced heart failure in the rat. Cardiovasc Pathol. 1999; 8(6): 315-323.

41. Regitz-Zagrosek V., Friedel N., Heymann A., Bauer P., Neuss M., Rolfs A., Steffen C., Hildebrandt A., Hetzer R., Fleck E. Regulation, chamber localization, and subtype distribution of angiotensin II receptors in human hearts. Circulation. 1995; 91(5): 1461-1471.

42. Sadoshima J., Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Circ Res. 1993; 73(3): 413-423.

43. Weinberger M.H., Aoi W., Henry D.P. Direct effect of betaadrenergic stimulation on renin release by the rat kidney slice in vitro. Circ Res. 1975; 37(3): 318-324.

44. Nakamaru M., Jackson E.K., Inagami T. Beta-adrenoceptormediated release of angiotensin II from mesenteric arteries. Am J Physiol. 1986; 250(1): H144-H148.

45. Dostal D.E., Booz G.W., Baker K.M. Regulation of angiotensinogen gene expression and protein in neonatal rat cardiac fibroblasts by glucocorticoid and betaadrenergic stimulation. Basic Res Cardiol. 2000; 95(6): 485-490.

46. Hori Y., Touei D., Saitoh R., Yamagishi M., Kanai K., Hoshi F., Itoh N. The aldosterone receptor antagonist eplerenone inhibits isoproterenol-induced collagen-I and 11β-HSD1 expression in rat cardiac fibroblasts and the left ventricle. Biol Pharm Bull. 2017; 40(10): 1716-1723.

47. Güder G., Bauersachs J., Frantz S., Weismann D., Allolio B., Ertl G., Angermann C.E., Störk S. Complementary and incremental mortality risk prediction by cortisol and aldosterone in chronic heart failure. Circulation. 2007; 115(13): 1754-1761.

48. Pitt B., Zannad F., Remme W.J., Cody R., Castaigne A., Perez A., Palensky J., Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341(10): 709-717.

49. Pitt B., Remme W., Zannad F., Neaton J., Martinez F., Roniker B., Bittman R., Hurley S., Kleiman J., Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348(14): 1309-1321.

50. Brown N.J. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol. 2013: 9(8): 459-469.

51. Garlie J.B., Hamid T., Gu Y., Ismahil M.A., Chandrasekar B., Prabhu S.D. Tumor necrosis factor receptor 2 signaling limits β-adrenergic receptor-mediated cardiachypertrophy in vivo. Basic Res Cardiol. 2011; 106(6): 1193- 1205.

52. Tanriverdi L.H., Parlakpinar H., Ozhan O., Ermis N., Polat A., Vardi N., Tanbek K., Yildiz A., Acet A. Inhibition of NADPH oxidase by apocynin promotes myocardial antioxidant response and prevents isoproterenol-induced myocardial oxidative stress in rats. Free Radic Res. 2017; 51(9-10): 772-786.

53. Murray D.R., Prabhu S.D., Chandrasekar B. Chronic beta-adrenergic stimulation induces myocardial proinflammatory cytokine expression. Circulation. 2000; 101(20): 2338-2341.

54. Bogoyevitch M.A., Andersson M.B., Gillespie-Brown J., Clerk A., Glennon P.E., Fuller S.J., Sugden P.H. Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy. Biochem J. 1996; 314(Pt 1): 115-121.

55. Zou Y., Yao A., Zhu W., Kudoh S., Hiroi Y., Shimoyama M., Uozumi H., Kohmoto O., Takahashi T., Shibasaki F., Nagai R., Yazaki Y., Komuro I. Isoproterenol activates extracellular signalregulated protein kinases in cardiomyocytes through calcineurin. Circulation. 2001; 104(1): 102-108.

56. Takemoto Y., Yoshiyama M., Takeuchi K., Omura T., Komatsu R., Izumi Y., Kim S., Yoshikawa J. Increased JNK, AP-1 and NF-kB binding activities in isoproterenolinduced cardiac remodeling. J Mol Cell Cardiol. 1999; 31(11): 2017-2030.

57. Brand T., Sharma H.S., Schaper W. Expression of nuclear proto-oncogenes in isoproterenol-induced cardiac hypertrophy. J Mol Cell Cardiol. 1993; 25(11): 1325-1337.

58. Robbins R.J., Swain J.L. C-myc protooncogene modulates cardiac hypertrophic growth in transgenic mice. Am J Physiol. 1992; 262(2): H590-H597.

59. Zimmer H.G. Catecholamine-induced cardiac hypertrophy: significance of proto-oncogene expression. J Mol Med. 1997; 75(11-12): 849-859.

60. Bishopric N.H., Jayasena V., Webster K.A. Positive regulation of the skeletal alpha-actin gene by Fos and Jun in cardiac myocytes. J Biol Chem. 1992; 267(35): 2535-2554.

61. Iwaki K., Sukhatme V., Shubeita H.E., Chien K.R. Alpha- and beta-adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. J Biol Chem. 1990; 265(23): 13809-13817.

62. Daaka Y., Luttrell L.M., Lefkowitz R.J. Switching of the coupling of the beta2-adrenergic receptor to different G-proteins by protein kinase A. Nature. 1997; 390(6655): 88-91.

63. Zou Y., Komuro I., Yamazaki T., Kudoh S., Uozumi H., Kadowaki T., Yazaki Y. Both Gs and Gi proteins are critically involved in isoproterenol-induced cardiomyocyte hypertrophy. J Biol Chem. 1999; 274(14): 9760-9770.

64. Oudit G.Y., Crackower M.A., Eriksson U., Sarao R., Kozieradzki I., Sasaki T., Irie-Sasaki J., Gidrewicz D., Rybin V.O., Wada T., Steinberg S.F., Backx P.H., Penninger J.M. Phosphoinositide 3-kinase-deficient mice are protected from isoproterenol-induced heart failure. Circulation. 2003; 108(17): 2147-2152.

65. Zhang G.-X., Kimura S., Nishiyama A., Shokoji T., Rahman M., Yao L., Nagai Y., Fujisawa Y., Miyatake A., Abe Y. Cardiac oxidative stress in acute and chronic isoproterenol-infused rats. Cardiovasc Res. 2005; 65(1): 230-238.

66. Haider A.W., Larson M.G., Benjamin E.J., Levy D. Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death. J Am Coll Cardiol. 1998; 32(5): 1454-1459.