Effects of exercise training on cardiovascular adrenergic system (original) (raw)

Abstract

In heart failure (HF), exercise has been shown to modulate cardiac sympathetic hyperactivation which is one of the earliest features of neurohormonal derangement in this syndrome and correlates with adverse outcome. An important molecular alteration related to chronic sympathetic overstimulation in HF is represented by cardiac β-adrenergic receptor (β-AR) dysfunction. It has been demonstrated that exercise reverses β-AR dysfunction by restoring cardiac receptor membrane density and G-protein-dependent adenylyl cyclase activation. In particular, several evidence indicate that exercise reduces levels of cardiac G-protein coupled receptor kinase-2 (GRK2) which is known to be involved in both β1-AR and β2-AR dysregulation in HF. Similar alterations of β-AR system have been described also in the senescent heart. It has also been demonstrated that exercise training restores adrenal GRK2/α-2AR/catecholamine (CA) production axis. At vascular level, exercise shows a therapeutic effect on age-related impairment of vascular reactivity to adrenergic stimulation and restores β-AR-dependent vasodilatation by increasing vascular β-AR responsiveness and reducing endothelial GRK2 activity. Sympathetic nervous system overdrive is thought to account for >50% of all cases of hypertension and a lack of balance between parasympathetic and sympathetic modulation has been observed in hypertensive subjects. Non-pharmacological, lifestyle interventions have been associated with reductions in SNS overactivity and blood pressure in hypertension. Several evidence have highlighted the blood pressure lowering effects of aerobic endurance exercise in patients with hypertension and the significant reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining the favorable effects of exercise on blood pressure control.

Loading...

Loading Preview

Sorry, preview is currently unavailable. You can download the paper by clicking the button above.

References (104)

  1. American College of Sports Medicine. (1993). Position stand. Physical activ- ity, physical fitness, and hypertension. Med. Sci. Sports Exerc. 25, i-x. doi: 10.1249/00005768-199310000-00024
  2. Anderson, E. A., Sinkey, C. A., Lawton, W. J., and Mark, A. L. (1989). Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings. Hypertension 14, 177-183. doi: 10.1161/01.HYP.14.2.177
  3. Baron, A. D., Brechtel-Hook, G., Johnson, A., and Hardin, D. (1993). Skeletal mus- cle blood flow. A possible link between insulin resistance and blood pressure. Hypertension 21, 129-135. doi: 10.1161/01.HYP.21.2.129
  4. Belardinelli, R., Georgiou, D., Cianci, G., and Purcaro, A. (1999). Randomized, con- trolled trial of long-term moderate exercise training in chronic heart failure: effects on functional capacity, quality of life, and clinical outcome. Circulation 99, 1173-1182. doi: 10.1161/01.CIR.99.9.1173
  5. Böhm, M., Dorner, H., Htun, P., Lensche, H., Platt, D., and Erdmann, E. (1993). Effects of exercise on myocardial adenylate cyclase and Gi alpha expression in senescence. Am. J. Physiol. 264, H805-H814.
  6. Bristow, M. R., Ginsberg, R., Umans, V., Fowler, M., Minobe, W., Rasmussen, R., et al. (1986). β1-and β2-Adrenergic receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective b1 receptor down-regulation in heart failure. Circ. Res. 59, 297-309. doi: 10.1161/01.RES.59.3.297
  7. Brodde, O. E., Zerkowski, H. R., Schranz, D., Broede-Sitz, A., Michel-Reher, M., Schäfer-Beisenbusch, E., et al. (1995a). Age-dependent changes in the beta- adrenoceptor-G-protein(s)-adenylyl cyclase system in human right atrium. J. Cardiovasc. Pharmacol. 26, 20-26. doi: 10.1097/00005344-199507000-00004
  8. Brodde, O. E., Michel, M. C., and Zerkowski, H. R. (1995b). Signal trans- duction mechanisms controlling cardiac contractility and their alterations in chronic heart failure. Cardiovasc. Res. 30, 570-584. doi: 10.1016/S0008- 6363(95)00152-2
  9. Cabassi, A., Vinci, S., Calzolari, M., Bruschi, G., and Borghetti, A. (1998). Regional sympathetic activity in pre-hypertensive phase of spontaneously hypertensive rats. Life Sci. 62, 1111-1118. doi: 10.1016/S0024-3205(98)00034-4
  10. Cannavo, A., Rengo, G., Liccardo, D., Pagano, G., Zincarelli, C., De Angelis, M. C., et al. (2013a). β1-adrenergic receptor and sphingosine-1-phosphate recep- tor 1 reciprocal down-regulation influences cardiac hypertrophic response and progression toward heart failure: protective role of S1PR1 cardiac gene therapy. Circulation 128, 1612-1622. doi: 10.1161/CIRCULATIONAHA.113. 002659
  11. Cannavo, A., Rengo, G., Liccardo, D., Pironti, G., Scimia, M. C., Scudiero, L., et al. (2013b). Prothymosin alpha protects cardiomyocytes against ischemia- induced apoptosis via preservation of Akt activation. Apoptosis 18, 1252-1261. doi: 10.1007/s10495-013-0876-9
  12. Chapman, J., Schutzer, W. E., Watts, V. J., and Mader, S. L. (1999). Impaired cholera toxin relaxation with age in rat aorta. J. Gerontol. A Biol. Sci. Med. Sci. 54, B154-B159. doi: 10.1093/gerona/54.4.B154
  13. Ciccarelli, M., Chuprun, J. K., Rengo, G., Gao, E., Wei, Z., Peroutka, R. J., et al. (2011). G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia. Circulation 123, 1953-1962. doi: 10.1161/CIRCULATIONAHA.110.988642
  14. Davies, C. H., Ferrara, N., and Harding, S. E. (1996). Beta-adrenoceptor func- tion changes with age of subject in myocytes from non-failing human ventricle. Cardiovasc. Res. 31, 152-156. doi: 10.1016/S0008-6363(95)00187-5
  15. de Waard, M. C., van der Velden, J., Bito, V., Ozdemir, S., Biesmans, L., Boontje, N. M., et al. (2007). Early exercise training normalizes myofilament function and attenuates left ventricular pump dysfunction in mice with a large myocardial infarction. Circ. Res. 100, 1079-1088. doi: 10.1161/01.RES.0000262655.16373.37
  16. Ehsani, A. A., Ogawa, T., Miller, T. R., Spina, R. J., and Jilka, S. M. (1991). Exercise training improves left ventricular systolic function in older men. Circulation 83, 96-103. doi: 10.1161/01.CIR.83.1.96
  17. Esler, M. (2010). The 2009 Carl Ludwig lecture: pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J. Appl. Physiol. 108, 227-237. doi: 10.1152/japplphysiol.00832.2009
  18. Esler, M., Jennings, G., Korner, P., Willett, I., Dudley, F., Hasking, G., et al. (1988). Assessment of human sympathetic nervous system activity from mea- surements of norepinephrine turnover. Hypertension 11, 3-20. doi: 10.1161/01. HYP.11.1.3
  19. Esler, M. D., Krum, H., Sobotka, P. A., Schlaich, M. P., Schmieder, R. E., and Bohm, M. (2010). Renal sympathetic denervation in patients with treatment- resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial. Lancet 376, 1903-1909. doi: 10.1016/S0140-6736(10)62039-9
  20. Femminella, G. D., Rengo, G., Pagano, G., de Lucia, C., Komici, K., Parisi, V., et al. (2013). β-adrenergic receptors and G protein-coupled receptor kinase-2 in Alzheimer's disease: a new paradigm for prognosis and therapy. J. Alzheimers Dis. 34, 341-347. doi: 10.3233/JAD-121813
  21. Ferrara, N., Böhm, M., Zolk, O., O'Gara, P., and Harding, S. E. (1997a). The role of Gi-proteins and beta-adrenoceptors in the age-related decline of contrac- tion in guinea-pig ventricular myocytes. J. Mol. Cell. Cardiol. 29, 439-448. doi: 10.1006/jmcc.1996.0397
  22. Ferrara, N., Davia, K., Abete, P., Rengo, F., and Harding, S. E. (1997b). Alterations in beta-adrenoceptor mechanisms in the aging heart. Relationship with heart failure. Aging 9, 391-403.
  23. Flynn, K. E., Piña, I. L., Whellan, D. J., Lin, L., Blumenthal, J. A., Ellis, S. J., et al. (2009). Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 301, 1451-1459. doi: 10.1001/jama.2009.457
  24. Francis, G. S., and Cohn, J. N. (1986). The autonomic nervous sys- tem in congestive heart failure. Annu. Rev. Med. 37, 235-247. doi: 10.1146/annurev.me.37.020186.001315
  25. Friberg, P., Karlsson, B., and Nordlander, M. (1988). Sympathetic and parasympa- thetic influence on blood pressure and heart rate variability in Wistar-Kyoto and spontaneously hypertensive rats. J. Hypertens. Suppl. 6, S58-S60.
  26. Gademan, M. G., Swenne, C. A., Verwey, H. F., van der Laarse, A., Maan, A. C., van de Vooren, H., et al. (2007). Effect of exercise training on autonomic derange- ment and neurohumoral activation in chronic heart failure. J. Card. Fail. 13, 294-303. doi: 10.1016/j.cardfail.2006.12.006
  27. Gaudron, P., Hu, K., Schamberger, R., Budin, M., Walter, B., and Ertl, G. (1994). Effect of endurance training early or late after coronary artery occlu- sion on left ventricular remodeling, hemodynamics, and survival in rats with chronic transmural myocardial infarction. Circulation 89, 402-412. doi: 10.1161/01.CIR.89.1.402
  28. Georget, M., Mateo, P., Vandecasteele, G., Jurevicius, J., Lipskaia, L., Defer, N., et al. (2002). Augmentation of cardiac contractility with no change in L-type Ca2+ current in transgenic mice with a cardiac-directed expression of the human adenylyl cyclase type 8 (AC8). FASEB J. 16, 1636-1648. doi: 10.1096/fj.02- 0292fje
  29. Giallauria, F., Acampa, W., Ricci, F., Vitelli, A., Torella, G., Lucci, R., et al. (2013). Exercise training early after acute myocardial infarction reduces stress-induced hypoperfusion and improves left ventricular function. Eur. J. Nucl. Med. Mol. Imaging 40, 315-324. doi: 10.1007/s00259-012-2302-x
  30. Giallauria, F., Cirillo, P., Lucci, R., Pacileo, M., D'Agostino, M., Maietta, P., et al. (2010). Autonomic dysfunction is associated with high mobility group box-1 levels in patients after acute myocardial infarction. Atherosclerosis 208, 280-284. doi: 10.1016/j.atherosclerosis.2009.07.025
  31. Goodson, A. R., Leibold, J. M., and Gutterman, D. D. (1994). Inhibition of nitric oxide synthesis augments centrally induced sympathetic coronary vasoconstric- tion in cats. Am. J. Physiol. 267, H1272-H1278.
  32. Grassi, G. (1998). Role of the sympathetic nervous system in human hypertension. J. Hypertens. 16, 1979-1987. doi: 10.1097/00004872-199816121-00019
  33. Grassi, G., Colombo, M., Seravalle, G., Spaziani, D., and Mancia, G. (1998a). Dissociation between muscle and skin sympathetic nerve activity in essential hypertension, obesity, and congestive heart failure. Hypertension 31, 64-67. doi: 10.1161/01.HYP.31.1.64
  34. Grassi, G., Cattaneo, B. M., Seravalle, G., Lanfranchi, A., and Mancia, G. (1998b). Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension 31, 68-72. doi: 10.1161/01.HYP.31.1.68
  35. Grassi, G., Seravalle, G., Bertinieri, G., Turri, C., Dell'Oro, R., Stella, M. L., et al. (2000). Sympathetic and reflex alterations in systo-diastolic and systolic hyper- tension of the elderly. J. Hypertens. 18, 587-593.16(12 Pt 2), 1979-1987. doi: 10.1097/00004872-200018050-00012
  36. Gros, R., Chorazyczewski, J., Meek, M. D., Benovic, J. L., Ferguson, S. S., and Feldman, R. D. (2000). G-Protein-coupled receptor kinase activity in hyperten- sion: increased vascular and lymphocyte G-protein receptor kinase-2 protein expression. Hypertension 35, 38-42. doi: 10.1161/01.HYP.35.1.38
  37. Hambrecht, R., Gielen, S., Linke, A., Fiehn, E., Yu, J., Walther, C., et al. (2000). Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure: a randomized trial. JAMA 283, 3095-3101. doi: 10.1001/jama.283.23.3095
  38. Harding, V., Jones, L., Lefkowitz, R. J., Koch, W. J., and Rockman, H. A. (2001). Cardiac βARK1 inhibition prolongs survival and augments β blocker ther- apy in a mouse model of severe heart failure. Proc. Natl. Acad. Sci. U.S.A. 98, 5809-5814. doi: 10.1073/pnas.091102398
  39. Henriksen, E. J. (2002). Invited review: effects of acute exercise and exercise training on insulin resistance. J. Appl. Physiol. 93, 788-796. doi: 10.1152/japplphys- iol.01219.2001
  40. Huggett, R. J., Burns, J., Mackintosh, A. F., and Mary, D. A. (2004). Sympathetic neural activation in nondiabetic metabolic syndrome and its further augmentation by hypertension. Hypertension 44, 847-852. doi: 10.1161/01.HYP.0000147893.08533.d8
  41. Hunt, S. A., Abraham, W. T., Chin, M. H., Feldman, A. M., Francis, G. S., Ganiats, T. G., et al. (2005). ACC/AHA (2005). Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Update the 2001 Guidelines for the evalu- ation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the international society for Heart and Lung Transplantation: endorsed by the Heart rhythm society. Circulation 112, e154-e235. doi: 10.1161/CIRCULATIONAHA.105.167586
  42. Iaccarino, G., Barbato, E., Cipolletta, E., De Amicis, V., Margulies, K. B., Leosco, D., et al. (2005). Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure. Eur. Heart J. 26, 1752-1758. doi: 10.1093/eur- heartj/ehi429
  43. Iaccarino, G., Tomhave, E. D., Lefkowitz, R. J., and Koch, W. J. (1998). Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by β-adrenergic receptor stimulation and blockade. Circulation 98, 1783-1789. doi: 10.1161/01.CIR.98.17.1783
  44. Judy, W. V., and Farrell, S. K. (1979). Arterial baroreceptor reflex control of sym- pathetic nerve activity in the spontaneously hypertensive rat. Hypertension 1, 605-614. doi: 10.1161/01.HYP.1.6.605
  45. Julius, S., Gudbrandsson, T., Jamerson, K., Tariq Shahab, S., and Andersson, O. (1991). The hemodynamic link between insulin resistance and hypertension. J. Hypertens. 9, 983-986. doi: 10.1097/00004872-199111000-00001
  46. Julius, S., and Nesbitt, S. (1996). Sympathetic overactivity in hypertension. A mov- ing target. Am. J. Hypertens. 9, 113S-120S. doi: 10.1016/0895-7061(96)00287-7
  47. Kaye, D. M., Lefkovitz, J., Jennings, G., Bergin, P., Broughton, A., and Esler, M. D. (1995). Adverse consequences of increased cardiac sympathetic activity in the failing human heart. J. Am. Coll. Cardiol. 26, 1257-1263. doi: 10.1016/0735- 1097(95)00332-0
  48. Kilts, J. D., Akazawa, T., Richardson, M. D., and Kwatra, M. M. (2002). Age increases cardiac G alphai2 expression, resulting in enhanced cou- pling to G protein-coupled receptors. J. Biol. Chem. 277, 31257-31262. doi: 10.1074/jbc.M203640200
  49. Koch, W. J., Rockman, H. A., Samama, P., Hamilton, R. A., Bond, R. A., Milano, C. A., et al. (1995). Cardiac function in mice overexpressing the β-adrenergic receptor kinase or a βARK inhibitor. Science 268, 1350-1353. doi: 10.1126/sci- ence.7761854
  50. Kohno, K., Matsuoka, H., Takenaka, K., Miyake, Y., Okuda, S., Nomura, G., et al. (2000). Depressor effect by exercise training is associated with amelioration of hyperinsulinemia and sympathetic overactivity. Intern. Med. 39, 1013-1019. doi: 10.2169/internalmedicine.39.1013
  51. Korner, P., Bobik, A., Oddie, C., and Friberg, P. (1993). Sympathoadrenal sys- tem is critical for structural changes in genetic hypertension. Hypertension 22, 243-252. doi: 10.1161/01.HYP.22.2.243
  52. Krum, H., Schlaich, M., Whitbourn, R., Sobotka, P. A., Sadowski, J., Bartus, K., et al. (2009). Catheter-based renal sympathetic denervation for resistant hyper- tension: a multicentre safety and proof-of-principle cohort study. Lancet 373, 1275-1281. doi: 10.1016/S0140-6736(09)60566-3
  53. Krum, H., Sobotka, P., Mahfoud, F., Bohm, M., Esler, M., and Schlaich, M. (2011). Device-based antihypertensive therapy: therapeutic modula- tion of the autonomic nervous system. Circulation 123, 209-215. doi: 10.1161/CIRCULATIONAHA.110.971580
  54. Lambert, E., Straznicky, N., Schlaich, M., Esler, M., Dawood, T., Hotchkin, E., et al. (2007). Differing pattern of sympathoexcitation in normal- weight and obesity related hypertension. Hypertension 50, 862-868. doi: 10.1161/HYPERTENSIONAHA.107.094649
  55. Laterza, M. C., de Matos, L. D., Trombetta, I. C., Braga, A. M., Roveda, F., Alves, M. J., et al. (2007). Exercise training restores baroreflex sensitiv- ity in never-treated hypertensive patients. Hypertension 49, 1298-1306. doi: 10.1161/HYPERTENSIONAHA.106.085548
  56. Leosco, D., Iaccarino, G., Cipolletta, E., De Santis, D., Pisani, E., Trimarco, V., et al. (2003). Exercise restores beta-adrenergic vasorelaxation in aged rat carotid arteries. Am. J. Physiol. Heart Circ. Physiol. 285, H369-H374. doi: 10.1152/ ajpheart.00019.2003
  57. Leosco, D., Rengo, G., Iaccarino, G., Filippelli, A., Lymperopoulos, A., Zincarelli, C., et al. (2007). Exercise and β-blocker treatment ameliorate age-impaired β-adrenergic receptor signaling and enhance cardiac responsiveness to adren- ergic stimulation. Am. J. Physiol. Heart Circ. Physiol. 293, H1596-H1603. doi: 10.1152/ajpheart.00308.2007
  58. Leosco, D., Rengo, G., Iaccarino, G., Golino, L., Marchese, M., Fortunato, F., et al. (2008). Exercise promotes angiogenesis and improves beta-adrenergic receptor signalling in the post ischaemic failing rat heart. Cardiovasc. Res. 78, 385-394. doi: 10.1093/cvr/cvm109
  59. Levy, N. W., Ng, M., Martin, P., and Zieske, H. (1966). Sympathetic and parasym- pathetic interactions upon the left ventricle of the dog. Circ. Res. 19, 5-10. doi: 10.1161/01.RES.19.1.5
  60. Lundin, S., Ricksten, S. E., and Thoren, P. (1984). Renal sympathetic activity in spontaneously hypertensive rats and normotensive controls, as studied by three different methods. Acta Physiol. Scand. 120, 265-272. doi: 10.1111/j.1748- 1716.1984.tb00133.x
  61. Lymperopoulos, A., Rengo, G., Funakoshi, H., Eckhart, A. D., and Koch, W. J. (2007a). Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure. Nat. Med. 13, 315-323. doi: 10.1038/nm1553
  62. Lymperopoulos, A., Rengo, G., and Koch, W. J. (2007b). Adrenal adrenoceptors in heart failure: fine-tuning cardiac stimulation. Trends Mol. Med. 13, 503-511. doi: 10.1016/j.molmed.2007.10.005
  63. Lymperopoulos, A., Rengo, G., and Koch, W. J. (2012). GRK2 inhibition in heart failure: something old, something new. Curr. Pharm. Des. 18, 186-191. doi: 10.2174/138161212799040510
  64. MacDonnell, S. M., Kubo, H., Crabbe, D. L., Renna, B. F., Reger, P. O., Mohara, J., et al. (2005). Improved myocardial beta-adrenergic responsiveness and sig- naling with exercise training in hypertension. Circulation 111, 3420-3428. doi: 10.1161/CIRCULATIONAHA.104.505784
  65. Marciano, C., Galderisi, M., Gargiulo, P., Acampa, W., D'Amore, C., Esposito, R., et al. (2012). Effects of type 2 diabetes mellitus on coronary microvascular func- tion and myocardial perfusion in patients without obstructive coronary artery disease. Eur. J. Nucl. Med. Mol. Imaging 39, 1199-1206. doi: 10.1007/s00259- 012-2117-9
  66. Mueller, P. J. (2007). Exercise training attenuates increases in lumbar sympathetic nerve activity produced by stimulation of the rostral ventrolateral medulla. J. Appl. Physiol. 102, 803-813. doi: 10.1152/japplphysiol.00498.2006
  67. Musch, T. I., Moore, R. L., Leathers, D. J., Bruno, A., and Zelis, R. (1986). Endurance training in rats with chronic heart failure induced by myocardial infarction. Circulation 74, 431-441. doi: 10.1161/01.CIR.74.2.431
  68. Paolillo, S., Rengo, G., Pagano, G., Pellegrino, T., Savarese, G., Femminella, G. D., et al. (2013). Impact of diabetes on cardiac sympathetic innervation in patients with heart failure: a 123I meta-iodobenzylguanidine (123I MIBG) scintigraphic study. Diabetes Care 36, 2395-2401. doi: 10.2337/dc12-2147
  69. Patel, K. P., Zhang, K., Zucker, I. H., and Krukoff, T. L. (1996). Decreased gene expression of neuronal nitric oxide synthase in hypothalamus and brainstem of rats in heart failure. Brain Res. 734, 109-115. doi: 10.1016/0006-8993(96) 00620-8
  70. Petrofski, J. P., and Koch, W. J. (2003). The β-adrenergic receptor kinase (βARK1) in heart failure. J. Mol. Cell. Cardiol. 35, 1167-1174. doi: 10.1016/S0022- 2828(03)00243-8
  71. Piepoli, M. F., Davos, C., Francis, D. P., Coats, A. J., and ExTraMATCH Collaborative. (2004). Exercise training metaanalysis of trials in patients with chronic heart failure (ExTraMATCH). BMJ 328, 189-195. doi: 10.1136/bmj.328.7441.711-b
  72. Raake, P. W., Vinge, L. E., Gao, E., Boucher, M., Rengo, G., Chen, X., et al. (2008). G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ. Res. 103, 413-422. doi: 10.1161/CIRCRESAHA.107.168336
  73. Rengo, G., Leosco, D., Zincarelli, C., Marchese, M., Corbi, G., Liccardo, D., et al. (2010). Adrenal GRK2 lowering is an underlying mechanism for the beneficial sympathetic effects of exercise training in heart failure. Am. J. Physiol. Heart Circ. Physiol. 298, H2032-H2038. doi: 10.1152/ajpheart.00702.2009
  74. Rengo, G., Lymperopoulos, A., Leosco, D., and Koch, W. J. (2011). GRK2 as a novel gene therapy target in heart failure. J. Mol. Cell. Cardiol. 50, 785-792. doi: 10.1016/j.yjmcc.2010.08.014
  75. Rengo, G., Lymperopoulos, A., Zincarelli, C., Donniacuo, M., Soltys, S., Rabinowitz, J. E., et al. (2009). Myocardial AAV6-βARKct gene therapy improves cardiac function and normalizes the neurohor- monal axis in chronic heart failure. Circulation 119, 89-98. doi: 10.1161/CIRCULATIONAHA.108.803999
  76. Rengo, G., Perrone-Filardi, P., Femminella, G. D., Liccardo, D., Zincarelli, C., de Lucia, C., et al. (2012a). Targeting the β-adrenergic receptor system through G- protein-coupled receptor kinase 2: a new paradigm for therapy and prognostic evaluation in heart failure: from bench to bedside. Circ. Heart Fail. 5, 385-391. doi: 10.1161/CIRCHEARTFAILURE.112.966895
  77. Rengo, G., Femminella, G. D., Liccardo, D., de Lucia, C., Pirozzi, E., Pagano, G., et al. (2012b). From bench to bedside: new insights into the treatment of heart failure. G. Ital. Cardiol. 13, 254-262. doi: 10.1714/1056.11557
  78. Rengo, G., Zincarelli, C., Femminella, G. D., Liccardo, D., Pagano, G., de Lucia, C., et al. (2012c). Myocardial β(2)-adrenoceptor gene delivery promotes coor- dinated cardiac adaptive remodelling and angiogenesis in heart failure. Br. J. Pharmacol. 166, 2348-2361. doi: 10.1111/j.1476-5381.2012.01954.x
  79. Rengo, F., Parisi, V., Rengo, G., Femminella, G. D., Rengo, C., Zincarelli, C., et al. (2012d). Instruments for geriatric assessment: new multidimensional assess- ment approaches. J. Nephrol. 25(Suppl. 19), S73-S78. doi: 10.5301/jn.5000164
  80. Rengo, G., Lymperopoulos, A., Zincarelli, C., Femminella, G., Liccardo, D., Pagano, G., et al. (2012e). Blockade of β-adrenoceptors restores the GRK2-mediated adrenal α(2) -adrenoceptor-catecholamine production axis in heart failure. Br. J. Pharmacol. 166, 2430-2440. doi: 10.1111/j.1476-5381.2012.01972.x
  81. Rengo, G., Pagano, G., Squizzato, A., Moja, L., Femminella, G. D., de Lucia, C., et al. (2013a). Oral anticoagulation therapy in heart failure patients in sinus rhythm: a systematic review and meta-analysis. PLoS ONE 8:e52952. doi: 10.1371/journal.pone.0052952
  82. Rengo, G., Cannavo, A., Liccardo, D., Zincarelli, C., de Lucia, C., Pagano, G., et al. (2013b). Vascular endothelial growth factor blockade prevents the beneficial effects of β-blocker therapy on cardiac function, angiogenesis and remodeling in heart failure. Circ. Heart Fail. doi: 10.1161/CIRCHEARTFAILURE.113.000 329. [Epub ahead of print].
  83. Rengo, G., Galasso, G., Femminella, G. D., Parisi, V., Zincarelli, C., Pagano, G., et al. (2013c). Reduction of lymphocyte G protein-coupled receptor kinase-2 (GRK2) after exercise training predicts survival in patients with heart failure. Eur. J. Prev. Cardiol. doi: 10.1177/2047487313491656. [Epub ahead of print].
  84. Rinaldi, B., Corbi, G., Boccuti, S., Filippelli, W., Rengo, G., Leosco, D., et al. (2006). Exercise training affects age-induced changes in SOD and heat shock protein expression in rat heart. Exp. Gerontol. 41, 764-770. doi: 10.1016/j.exger.2006.05.008
  85. Rockman, H. A., Chien, K. R., Choi, D.-J., Iaccarino, G., Hunter, J. J., Ross, J. Jr., et al. (1998). Expression of a β-adrenergic receptor kinase 1 inhibitor prevents the development of heart failure in gene targeted mice. Proc. Natl. Acad. Sci. U.S.A. 95, 7000-7005. doi: 10.1073/pnas.95.12.7000
  86. Rockman, H. A., Koch, W. J., and Lefkowitz, R. J. (2002). Seven-transmembrane- spanning receptors and heart function. Nature 415, 206-212. doi: 10.1038/415206a
  87. Salazar, N. C., Vallejos, X., Siryk, A., Rengo, G., Cannavo, A., Liccardo, D., et al. (2013). GRK2 blockade with betaARKct is essential for cardiac beta2-adrenergic receptor signaling towards increased contractility. Cell Commun. Signal. 11, 64. doi: 10.1186/1478-811X-11-64
  88. Savarese, G., Trimarco, B., Dellegrottaglie, S., Prastaro, M., Gambardella, F., Rengo, G., et al. (2013). Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2, 686 patients in 12 randomized trials. PLoS ONE 8:e58287. doi: 10.1371/journal.pone.0058287
  89. Schlaich, M. P., Lambert, E., Kaye, D., Krozowski, Z., Campbell, D. J., Lambert, G., et al. (2004). Sympathetic augmentation in hypertension. Role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation. Hypertension 43, 169-175. doi: 10.1161/01.HYP.0000103160.35395.9E
  90. Schutzer, W. E., Reed, J. F., Bliziotes, M., and Mader, S. L. (2001). Upregulation of G protein-linked receptor kinases with advancing age in rat aorta. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R897-R903.
  91. Seals, D. R., and Esler, M. D. (2000). Human ageing and sympathoadrenal system. J. Physiol. 528, 407-417. doi: 10.1111/j.1469-7793.2000.00407.x
  92. Shah, A. S., White, D. C., Emani, S., Kypson, A. P., Lilly, R. E., Wilson, K., et al. (2001). In vivo ventricular gene delivery of a β-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation 103, 1311-1316. doi: 10.1161/01.CIR.103.9.1311
  93. Simms, A. E., Paton, J. F., Pickering, A. E., and Allen, A. M. (2009). Amplified respiratory-sympathetic coupling in the spontaneously hypertensive rat: does it contribute to hypertension. J. Physiol. 587(Pt 3), 597-610. doi: 10.1113/jphys- iol.2008.165902
  94. Smith, P. A., Graham, L. N., Mackintosh, A. F., Stoker, J. B., and Mary, D. A. (2002). Sympathetic neural mechanisms in white-coat hypertension. J. Am. Coll. Cardiol. 40, 126-132. doi: 10.1016/S0735-1097(02)01931-9
  95. Smith, P. A., Graham, L. N., Mackintosh, A. F., Stoker, J. B., and Mary, D. A. (2004). Relationship between central sympathetic activity and stages of human hyper- tension. Am. J. Hypertens. 17, 217-222. doi: 10.1016/j.amjhyper.2003.10.010
  96. Spina, R. J., Turner, M. J., and Ehsani, A. A. (1998). Beta-adrenergic-mediated improvement in left ventricular function by exercise training in older men. Am. J. Physiol. 274, H397-H404.
  97. Stratton, J. R., Cerqueira, M. D., Schwartz, R. S., Levy, W. C., Veith, R. C., Kahn, S. E., et al. (1992). Differences in cardiovascular responses to isoproterenol in relation to age and exercise training in healthy men. Circulation 86, 504-512. doi: 10.1161/01.CIR.86.2.504
  98. Stratton, J. R., Levy, W. C., Cerqueira, M. D., Schwartz, R. S., and Abrass, I. B. (1994). Cardiovascular responses to exercise. Effects of aging and exer- cise training in healthy men. Circulation 89, 1648. doi: 10.1161/01.CIR. 89.4.1648
  99. Ungerer, M., Bohm, M., Elce, J. S., Erdmann, E., and Lohse, M. J. (1993). Altered expression of beta-adrenergic receptor kinase and beta 1-adren- ergic receptors in the failing human heart. Circulation 87, 454-463. doi: 10.1161/01.CIR.87.2.454
  100. van Tol, B. A., Huijsmans, R. J., Kroon, D. W., Schothorst, M., and Kwakkel, G. (2006). Effects of exercise training on cardiac performance, exercise capacity and quality of life in patients with heart failure: a meta-analysis. Eur. J. Heart Fail. 8, 841-850. doi: 10.1016/j.ejheart.2006.02.013
  101. Wustmann, K., Kucera, J. P., Scheffers, I., Mohaupt, M., Kroon, A. A., de Leeuw, P. W., et al. (2009). Effects of chronic baroreceptor stimulation on the auto- nomic cardiovascular regulation in patients with drug-resistant arterial hyper- tension. Hypertension 54, 530-536. doi: 10.1161/HYPERTENSIONAHA.109. 134023
  102. Xiao, R. P., Cheng, H., Zhou, Y. Y., Kuschel, M., and Lakatta, E. G. (1999). Recent advances in cardiac beta(2)-adrenergic signal transduction. Circ. Res. 85, 1092-1100. doi: 10.1161/01.RES.85.11.1092
  103. Xiao, R. P., Spurgeon, H. A., O'Connor, F., and Lakatta, E. G. (1994). Age-associated changes in beta adrenergic modulation on rat cardiac excitation-contraction coupling. J. Clin. Invest. 94, 2051-2059. doi: 10.1172/JCI117559
  104. Xiao, R. P., Tomhave, E. D., Wang, D. J., Ji, X., Boluyt, M. O., Cheng, H., et al. (1998). Age-associated reductions in cardiac beta1-and beta2-adrenergic responses without changes in inhibitory G proteins or receptor kinases. J. Clin. Invest. 101, 1273-1282. doi: 10.1172/JCI1335