Effects of exercise training on cardiovascular adrenergic system

Frontiers in Physiology

Volumn 4, Issue , 2013, Pages

  Leosco, Dario ^a   Parisi, Valentina ^a   Femminella, Grazia D ^a   Formisano, Roberto ^a   Petraglia, Laura ^a   Allocca, Elena ^a   Bonaduce, Domenico ^a  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

Adrenergic system; Aging process; Exercise; Heart failure; Systemic hypertension

Indexed keywords

ALPHA 2 ADRENERGIC RECEPTOR; BETA 1 ADRENERGIC RECEPTOR; BETA 2 ADRENERGIC RECEPTOR; G PROTEIN COUPLED RECEPTOR KINASE 2;

ADRENERGIC STIMULATION; ADRENERGIC SYSTEM; AEROBIC EXERCISE; BLOOD PRESSURE REGULATION; BLOOD VESSEL REACTIVITY; CARDIOVASCULAR ADRENERGIC SYSTEM; ENDURANCE TRAINING; ENZYME ACTIVITY; EXERCISE; HEART FAILURE; HUMAN; HYPERACTIVITY; NONHUMAN; REVIEW; VASCULAR DISEASE; VASODILATATION;

EID: 84992193817     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2013.00348     Document Type: Review

References (104)

1. American College of Sports Medicine. (1993). Position stand. Physical activity, 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 muscle 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, controlled 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). β 1-and β 2-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 transduction 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). β 1-adrenergic receptor and sphingosine-1-phosphate receptor 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 function 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 measurements 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 contraction 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 system 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 parasympathetic 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 derangement 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 occlusion 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 vasoconstriction 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 hypertension 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 hypertension: 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 β ARK1 inhibition prolongs survival and augments β blocker therapy 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/japplphysiol.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 evaluation 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/eurheartj/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 sympathetic 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 moving 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 coupling 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 β ARK inhibitor. Science 268, 1350-1353. doi: 10.1126/science.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 system 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 hypertension: 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 modulation 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 sensitivity 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 adrenergic 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 parasympathetic 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 signaling 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 function 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 (β ARK1) 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-β ARKct gene therapy improves cardiac function and normalizes the neurohormonal 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 coordinated 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 assessment 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 a(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.113.000329. [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/jphysiol.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 hypertension. 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 exercise 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-adrenergic 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 autonomic cardiovascular regulation in patients with drug-resistant arterial hypertension. 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.