Recent Developments on coronary microvasculopathy after heart transplantation: A new target in the therapy of cardiac allograft vasculopathy

Current Vascular Pharmacology

Volumn 10, Issue 2, 2012, Pages 206-215

  Tona, Francesco ^a   Marra, Martina Perazzolo ^a   Fedrigo, Marny ^a   Famoso, Giulia ^a   Bellu, Roberto ^a   Thiene, Gaetano ^a   Gerosa, Gino ^a   Angelini, Annalisa ^a   Iliceto, Sabino ^a  

^a UNIVERSITY OF PADOVA   (Italy)

Author keywords

Cardiac allograft vasculopathy; Diagnosis; Heart transplantation; Immunosuppression; Microcirculation; Rejection

Indexed keywords

CALCIUM CHANNEL BLOCKING AGENT; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENDOTHELIAL NITRIC OXIDE SYNTHASE; EVEROLIMUS; EZETIMIBE; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; PRAVASTATIN; RAPAMYCIN; SIMVASTATIN;

ANGIOCARDIOGRAPHY; ARTERY INTIMA PROLIFERATION; CARDIAC ALLOGRAFT VASCULOPATHY; CARDIOVASCULAR MAGNETIC RESONANCE; CAUSE OF DEATH; CELL ACTIVATION; CELL PROLIFERATION; CORONARY ARTERY BLOOD FLOW; CORONARY FLOW RESERVE; DOPPLER FLOWMETRY; EARLY DIAGNOSIS; ENDOTHELIUM INJURY; HEART MUSCLE FIBROSIS; HEART TRANSPLANTATION; HISTOPATHOLOGY; HUMAN; HYPERLIPIDEMIA; HYPERTENSION; IMMUNOSUPPRESSIVE TREATMENT; IMPAIRED GLUCOSE TOLERANCE; INFLAMMATION; INTRAVASCULAR ULTRASOUND; MICROCIRCULATION; PATHOPHYSIOLOGY; PERFUSION WEIGHTED IMAGING; POST TREATMENT SURVIVAL; POSTOPERATIVE COMPLICATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REOPERATION; REVIEW; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; SMOKING; SMOOTH MUSCLE FIBER; SURGICAL MORTALITY; SURGICAL RISK; TREATMENT OUTCOME; VASCULAR ENDOTHELIUM; VASCULAR SMOOTH MUSCLE;

CORONARY CIRCULATION; CORONARY VESSELS; DISEASE PROGRESSION; HEART DISEASES; HEART TRANSPLANTATION; HUMANS; MICROCIRCULATION; MICROVESSELS; PREDICTIVE VALUE OF TESTS; QUALITY OF LIFE; RISK FACTORS; SURVIVAL RATE; VASCULAR DISEASES;

EID: 84857125912     PISSN: 15701611     EISSN: 18756212     Source Type: Journal    
DOI: 10.2174/157016112799304987     Document Type: Review

References (109)

1. Patterson C, Patterson KB. The history of heart transplantation. Am J Med Sci 1997; 314: 190-7.
2. Carrel A, Guthrie CC. The transplantation of veins and organs. Am J Med 1905; 11: 1101-2.
3. Mann FC, Priestly JT, Markowitz J, Yates YM. Transplantation of the intact mammalian heart. Arch Surg 1933; 26: 219-24.
4. Demikhov VP. Experimental Transplantation of Vital Organs. New York: Consultants Bureau 1962;1-285.
5. Hurley EJ, Dong E Jr, Stofer RC, Shumway NE. Isotopic replacement of the totally excised canine heart. J Surg Res 1962; 2: 90-4.
6. Barnard CN. The operation. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. S Afr Med J 1967; 41: 1271-4.
7. Borel JF, Feurer C, Gubler HU, Stahelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 1976; 6: 468-75.
8. Griffith BP, Hardesty RL, Deeb GM, Starlz TE, Bahnson HT. Cardiac transplantation with cyclosporin A and prednisone. Ann Surg 1982; 196: 324-9.
9. Stehlik J, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult heart transplant report-2010. J Heart Lung Transplant 2009; 29: 1089-103.
10. Caforio ALP, Tona F, Belloni-Fortina A, et al. Immune and nonimmune predictors of cardiac allograft vasculopathy onset and severity: multivariate risk factor analysis and role of immunosuppression. Am J Transplant 2004; 4: 962-70.
11. Billingham ME. Histopathology of graft coronary disease. J Heart Lung Transplant 1992; 11 (pt 2): S38-S44.
12. Valantine HA, Rickenbacker P, Kemna M, et al. Metabolic abnormalities characteristic of dysmetabolic syndrome predict the development of transplant coronary artery disease: a prospective study. Circulation 2001; 103: 2144-52.
13. Avery RK. Cardiac allograft vasculopathy. N Engl J Med 2003; 349: 829-30.
14. Kobashigawa J, Tobis JM, Starling RC, et al. Multicenter intravascular ultrasound validation study among heart transplant recipients. J Am Coll Cardiol 2005; 45: 1532-7.
15. Rickenbacher PR, Pinto FJ, Lewis NP, et al. Prognostic importance of intimal thickness as measured by intracoronary ultrasound after cardiac transplantation. Circulation 1995; 92: 3445-52.
16. Mintz G, Nissen SE, Anderson WD, et al. ACC clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound sudies: a report of the American College of Cardiology task force on Clinical Expert Consensus Documents (Committee to develop a Clinical Expert Consensus Document on standards for acquisition, measurement and reporting of intravascular ultrasound sudies [IVUS]). J Am Coll Cardiol 2001; 37: 1478-92.
17. Fearon WF, Nakamura M, Lee DP, et al. Simultaneous assessment of fractional and coronary flow reserves in cardiac transplant recipients: physiologic investigation for transplant recipients (PITA study). Circulation 2003; 108: 1605-10.
18. Tona F, Caforio ALP, Montisci R, et al. Coronary flow reserve by contrast-enhanced echocardiography: a new non-invasive diagnostic tool for cardiac allograft vasculopathy. Am J Transplant 2006; 6: 998-1003.
19. Tona F, Caforio ALP, Montisci R, et al. Coronary flow velocity pattern and coronary flow reserve by contrast-enhanced transthoracic echocardiography predict long-term outcome in heart transplantation. Circulation 2006; 114 (suppl I): I49-55.
20. Tona F, Osto E, Tarantini G, et al. Coronary flow reserve by transthoracic echocardiography predicts epicardial intimal thickening in cardiac allograft vasculopathy. Am J Transplant 2010; 10: 1668-76.
21. Stoica SC, Cafferty F, Pauriah M, et al. The cumulative effect of acute rejection on development of cardiac allograft vasculopathy. J Heart Lung Transplant 2006; 25: 420-5.
22. Tambur AR, Pamboukian SV, Costanzo MR, et al. The presence of HLA-directed antibodies after heart transplantation is associated with poor allograft outcome. Transplantation 2005; 80: 1019-25.
23. Dunn MJ, Crisp SJ, Rose ML, Taylor PM, Yacoub MH. Antiendothelial antibodies and coronary artery disease after cardiac transplantation. Lancet 1992; 339: 1566-70.
24. Jurcevic S, Ainsworth ME, Pomerance A, et al. Antivimentin antibodies are an independent predictor of transplant associated coronary artery disease after cardiac transplantation. Transplantation 2001; 71: 886-92.
25. Anyanwu AC, Banner NR, Mitchell AG, Khaghani A, Yacoub MH. Low incidence and severity of transplant-associated coronary artery disease in heart transplant from live donors. J Heart Lung Transplant 2003; 22: 281-6.
26. Mehra MR, Uber PA, Ventura HO, Scott RL, Park MH. The impact of mode of donor brain death on cardiac allograft vasculopathy: an intravascular ultrasound study. J Am Coll Cardiol 2004; 43: 806-10.
27. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA 1989; 261: 3561-6.
28. Escobar A, Ventura HO, Stapleton DD, et al. Cardiac allograft vasculopathy assessed by intravascular ultrasonography and nonimmunologic risk factors. Am J Cardiol 1994; 74: 1042-6.
29. Radovancevic B, Poindexter S, Birovljev S, et al. Risk factors for development of accelerated coronary artery disease in cardiac transplant recipients. Eur J Cardiothorac Surg 1990; 4: 309-12.
30. Arbustini E, Roberts WC. Morphological observations in the epicardial coronary arteries and their surroundings late after cardiac transplantation (allograft vascular disease). Am J Cardiol 1996; 78: 814-20.
31. Lin H, Wilson JE, Kendall TJ, et al. Comparable proximal and distal severity of intimal thickening and size of epicardial coronary arteries in transplant arteriopathy of human cardiac allografts. J Heart Lung Transplant 1994; 13: 824-33.
32. Liu G, Butany J. Morphology of graft arteriosclerosis in cardiac transplant recipients. Hum Pathol 1992; 23: 768-73.
33. Botas J, Pinto FJ, Chenzbraun A, et al. Influence of preexistent donor coronary artery disease on the progression of transplant vasculopathy. An intravascular ultrasound study. Circulation 1995; 92: 1126-32.
34. Tsutsui H, Ziada KM, Schoenhagen P, et al. Lumen loss in transplant coronary artery disease is a biphasic process involving early intimal thickening and late constrictive remodeling: results from a 5-year serial intravascular ultrasound study. Circulation 2001; 104: 653-7.
35. Hayry P, Isoniemi H, Yilmaz S, et al. Chronic allograft rejection. Immunol Rev 1993; 134: 33-81.
36. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-9.
37. Libby p, Pober JS. Chronic rejection. Immunity 2001; 14: 387-97.
38. Kuo L, Chilian WM, Davis MJ. Interaction of pressure- and flowinduced responses in porcine coronary resi stance vessels. Am J Physiol 1991; 261 (6 Pt 2): H1706-15.
39. Schwartzkopff B, Motz W, Frenzel H, Vogt M, Knauer S, Strauer BE. Structural and functional alterations of the intramyocardial coronary arterioles in patients with arterial hypertension. Circulation 1993; 88: 993-1003.
40. Drakos SG, Kfoury AG, Hammond EH, et al. Impact of mechanical unloading on microvasculature and associated central remodeling features of the failing human heart. J Am Coll Cardiol 2010; 56: 382-91.
41. Clausell N, Butany J, Molossi S, et al. Abnormalities in intramyocardial arteries detected in cardiac transplant biopsy specimens and lack of correlation with abnormal intracoronary ultrasound or endothelial dysfunction in large epicardial coronary arteries. J Am Coll Cardiol 1995; 26: 110-9.
42. Hiemann NE, Wellnhofer E, Knosalla C, et al. Prognostic impact of microvasculopathy on survival after heart transplantation: evidence from 9713 endomyocardial biopsies. Circulation 2007; 116: 1274-82.
43. Escaned J, Flores A, Garcìa-Pavìa P, Segovia J, et al. Assessment of microcirculatory remodeling with intracoronary flow velocity and pressure measurements: validation with endomyocardial sampling in cardiac allografts. Circulation 2009; 120: 1561-8.
44. Valantine HA. Cardiac allograft vasculopathy: central role of endothelial injury leading to transplant "atheroma". Transplantation 2003; 76: 891-9.
45. Weiss M, Cooke JP. Cardiac allograft vasculopathy and dysregulation of the NO synthase pathway. Arterioscler Thromb Vasc Biol 2003; 23: 567-75.
46. Hollenberg SM, Klein LW, Parrillo JE et al. Coronary endothelial dysfunction after heart transplantation predicts allograft vasculopathy and cardiac death. Circulation 2001; 104: 3091-6.
47. Davies SF, Yeung AC, Meredith IT, et al. Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year posttransplant. Circulation 1996; 93: 457-62.
48. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term out come of coronary heart disease. Circulation 2000; 101: 1899-906.
49. Potluri SP, Mehra MR, Uber PA, Park MH, Scott RL, Ventura HO. Relationship among epicardial coronary disease, tissue myocardial perfusion, and serviva in heart transplantation. J Heart Lung Transplant 2005; 24: 1019-25.
50. Weis M, Peter-Wolf W, Mazzilli M, et al. Variations of segmental endothelium-dependent and endothelium-independent vasomotor tone after cardiac transplantation (qualitative changes in endothelial function). Am Heart J 1997; 134: 306-15.
51. Konig A, Spes CH, Schiele TM, et al. Coronary Doppler measurements do not predict progression of cardiac allograft vasculopathy: analysis by serial intracoronary Doppler, dobutamine stress echocardiography, and intracoronary ultrasound. J Heart Lung Transplant 2002; 21: 902-5.
52. Caiati C, Montaldo C, Zedda N, Bina A, Iliceto S. New noninvasive method for coronary flow reserve assessment: contrast-enhanced transthoracic second harmonic echo Doppler. Circulation 1999; 99: 771-8.
53. Caiati C, Montaldo C, Zedda N, et al. Validation of a new noninvasive method (contrast-enhanced transthoracic second harmonic echo Doppler) for the evaluation of coronary flow reserve: comparison with intracoronary Doppler flow wire. J Am Coll Cardiol 1999; 34: 1193-200.
54. Pennell DJ. Cardiovascular magnetic resonance. Circulation 2010; 121: 692-705.
55. Schwitter J, Wacker CM, van Rossum AC, et al. MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial. Eur Heart J 2008; 29: 480-9.
56. Nagel E, Klein C, Paetsch I, et al. Magnetic resonance perfusion measurements for the non-invasive detection of coronary artery disease. Circulation 2003; 108: 432-7.
57. Gerber BL, Raman SV, Nayak K, et al. Myocardial first-pass perfusion cardiovascular magnetic resonance: history, theory, and current state of the art. J Cardiovasc Magn Reson. 2008; 10: 18.
58. Lee DC, Simonetti OP, Harris KR, et al. Magnetic resonance vs. radionuclide pharmacological stress perfusion imaging for flow-limiting stenoses of varying severity. Circulation 2004; 110: 58-65.
59. Muehling OM, Wilke NM, Panse P, et al. Reduced myocardial perfusion reserve and transmural perfusion gradient in heart transplant arteriopathy assessed by Magnetic Resonance Imaging. J Am Coll Cardiol 2003; 42: 104-60.
60. Lim YJ, Nanto S, Masuyama T, et al. Visualization of subendocardial myocardial ischemia with myocardial contrast echocardiography in humans. Circulation 1989; 79: 233-44.
61. Van Rossum AC, Visser FC, Hofman MBM, Galjee MA, Westerhof N, Valk J. Global left ventricular perfusion: non-invasive measurement with cine MR imaging and phase velocity mapping of coronary venous outflow. Radiology 1992; 182: 685-91.
62. Kennedy K, Dick A, MD, Drangova M, et al. Magnetic resonance measurements of coronary flow reserve in heart transplant recipients: an exploratory study of the relationship to coronary angiographic findings. J Cardiovasc Magn Reson 2007; 9: 701-7.
63. Korosogloua G, Osman NF, Denglera TJ, et al. Strain-encoded cardiac magnetic resonance for the evaluation of chronic allograft vasculopathy in transplant recipients. Am J Transplant 2009; 9: 2587-96.
64. Taylor AJ, Vaddadi G, Pfluger H, et al. Diagnostic performance of multisequential cardiac magnetic resonance imaging in acute cardiac allograft rejection. Eur J Heart Fail 2010; 12: 45-51.
65. Steen H, Merten C, Refle S, et al. Prevalence of different gadolinium enhancement patterns in patients after heart transplantation. J Am Coll Cardiol 2008; 52: 1160-7.
66. Grimm M, Rinaldi M, Yonan NA, et al. Superior prevention of acute rejection by tacrolimus vs. cyclosporine in heart transplant recipients-a large European trial. Am J Transplant 2006; 6: 1387-97.
67. Dandel M, Hetzer R. Impact of immunosuppressive drugs on the development of cardiac allograft vasculopathy. Curr Vasc Pharmacol 2010; 8: 706-19.
68. Kobashigawa JA, Tobis JM, Mentzer RM, et al. Mycophenolate mofetil reduces intimal thickness by intravascular ultrasound after heart transplant: reanalysis of the multicenter trial. Am J Transplant 2006; 6: 993-7.
69. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003; 349: 847-58.
70. Fuchs U, Zittermann A, Hakim-Meibodi K, Börgermann J, Schulz U, Gummert JF. Everolimus plus dosage reduction of cyclosporine in cardiac transplant recipients with chronic kidney disease: a two-year follow-up study. Transplant Proc 2011; 43: 1839-46.
71. Mancini D, Pinney S, Burkhoff D, et al. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation 2003; 108: 48-53.
72. Marx MO, Jayaraman T, Go LO, Marks AR. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res 1995; 76: 412-17.
73. Raisanen-Sokolowski A, Vuoristo P, Myllarnieni M, Yilmaz S, Kallio E, Hayry P. Mycophenolate mofetil (MMF, RS-61443) inhibits inflammation and smooth muscle cell proliferation in rat aortic allografts. Transpl Immunol 1995; 3: 342-51.
74. Poon M, Marx SO, Gallo R, Badimon JJ, Taubman MB, Marks AR. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest 1996; 98: 2277-83.
75. Poston RS, Billingham M, Hoyt EG, et al. Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model. Circulation 1999; 100: 67-74.
76. Mehra MR, Ventura HO, Smart FW, Collins TJ, Ramee SR, Stapleton DD. An intravascular ultrasound study of the influence of angiotensin-converting enzyme inhibitors and calcium entry blockers on the development of cardiac allograft vasculopathy. Am J Cardiol 1995; 75: 853-4.
77. Schroeder JS, Gao SZ, Alderman EL, et al. A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. N Engl J Med 1993; 328: 164-70.
78. Wenke K, Meiser B, Thiery J, et al. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation 1997; 96: 1398-402.
79. Wenke K, Meiser B, Thiery J, et al. Simvastatin initiated early after heart transplantation:8-year prospective experience. Circulation 2003; 107: 93-7.
80. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995; 333: 621-7.
81. Shaw SM, Najam O, Khan U, Yonan N, Williams SG, Fildes JE. Ezetimibe and atorvastatin both immunoregulate CD4+ T cells from cardiac transplant recipients in vitro. Transpl Immunol 2009; 21: 179-82.
82. Crespo-Leiro MG, Paniagua MJ, Marzoa R, et al. The efficacy and safety of ezetimibe for treatment of dyslipidemia after heart trans-plantation. Transplant Proc 2008; 40: 3060-2.
83. Guisado Rasco A, Lage Gallé E, Sobrino Màrquez JM, et al. Safety and efficacy of ezetimibe in a sample of cardiac transplant patients. Transplant Proc 2008; 40: 3058-9.
84. Shimizu K, Aikawa M, Takayama K, Libby P, Mitchell RN. Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins. Circulation 2003; 108: 2113-20.
85. Kobashigawa JA, Moriguchi JD, Laks H, et al. Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. J Heart Lung Transplant 2005; 24: 1736-40.
86. Stojanovic I, Vrtovec B, Radovancevic B, et al. Survival, graft atherosclerosis, and rejection incidence in heart transplant recipients treated with statins: 5-year follow-up. J Heart Lung Transplant 2005; 24: 1235-8.
87. Kobashigawa JA. Statins and cardiac allograft vasculopathy after heart transplantation. Semin Vasc Med 2004; 4: 401-6.
88. Kobashigawa JA. Statins in solid organ transplantation: is there an immunosuppressive effect? Am J Transplant 2004; 4: 1013-8.
89. Valantine HA, Gao SZ, Menon SG, et al. Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: a post hoc analysis of a randomized, placebocontrolled study. Circulation 1999; 100: 61-6.
90. Valantine HA, Luikart H, Doyle R, et al. Impact of cytomegalovirus hyperimmune globulin on out come after cardiothoracic transplantation: a comparative study of combined prophylaxis with CMV hyperimmune globulin plus ganciclovir vs. ganciclovir alone. Transplantation 2001; 72: 1647-52.
91. Musci M, Loebe M, Wellnhofer E, et al. Coronary angioplasty, bypass surgery, and retransplantation in cardiac transplant patients with graft coronary disease. Thorac Cardiovasc Surg 1998; 46: 268-74.
92. Topkara VK, Dang NC, John R, et al. A decade experience of cardiac retransplantation in adult recipients. J Heart Lung Transplant 2005; 24: 1745-50.
93. Raichlin E, Kushwaha SS, Lennon RJ, et al. Features of cardiac allograft coronary endothelial dysfunction. Am J Cardiol 2009; 103: 1154-8.
94. Ramzy D, Wallen J, Badiwala MV, et al. Endothelin-1 antagonism and nitric oxide augmentation prevents cyclosporine-induced vasomotor impairment. J Heart Lung Transplant 2011; 30: 77-85.
95. ] Rigol M. Solanes N, Sionis A, et al. Effects of cyclosporine, tacrolimus and sirolimus on vascular changes related to immune response. J Heart Lung Transplant 2008; 27: 416-22.
96. Abd-Elrahman KS, El-Gowelli HM, Saad EI, Abdel-Galil AG, El-Mas MM. Role of PPAR gamma/nitric oxide synthase signaling in the cyclosporine-induced attenuation of endothelium-dependent renovascular vasodilation. J Cardiovasc Pharmacol 2010; 56: 195-202.
97. Lòpez-Ongil S, Hernàndez-Perera O, Navarro-Antolìn J, et al. Role of reactive oxygen species in the signalling cascade of cyclosporine A-mediated up-regulation of eNOS in vascular endothelial cells. Br J Pharmacol 1998; 124: 447-54.
98. Redondo-Horcajo M, Romero N, Martinez-Acedo P, et al. Cyclosporine A-induced nitration of tyrosine 34 MnSOD in endothelial cells: role of mitochondrial superoxide. Cardiovasc Res 2010; 87: 356-65.
99. Krauskopf A, Lhote P, Petermann O, Ruegg UT, Buetler TM. Cyclosporin A generates superoxide in smooth muscle cells. Free Radic Res 2005; 39: 913-19.
100. Cheng C, Tempel D, Oostlander A, et al. Rapamycin modulates the eNOS vs. shear stress relationship. Cardiovasc Res 2008; 78: 123-9.
101. Ramzy D, Rao V, Tumiati LC, et al. Role of endothelin-1 and nitric oxide bioavailability in transplant-related vascular injury: comparative effects of rapamycin and cyclosporine. Circulation 2006; 114 (1 Suppl): I214-9.
102. Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation 2004; 110: 2694-700.
103. Dambrin C, Klupp J, Bîrsan T, et al. Sirolimus (Rapamycin) monotherapy prevents graft vascular disease in non-human primate recipients of orthotopic aortic allografts. Circulation 2003; 107: 2369-74.
104. Sinha SS, Pham MX, Vagelos RH, et al. Effect of rapamycin therapy on coronary artery physiology early after cardiac transplantation. Am Heart J 2008; 155: 889.e1-889.e6.
105. Raichlin E, Prasad A, Kremers WK, et al. Sirolimus as primary immunosuppression is associated with improbe coronary vasomotor function compared with calcineurin inhibitors in stable cardiac transplant recipients. Eur Heart J 2009; 30: 1356-63.
106. Petrakopoulou P, Anthopoulou L, Muscholl M, et al. Coronary endothelial vasomotor function and vascular remodeling in heart transplant recipients randomized for tacrolimus or cyclosporine immunosuppression. J Am Coll Cardiol 2006; 47: 1622-9.
107. Costanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29: 914-56.
108. Eisen H. Long-term cardiovascular risk in transplantation-insights from the use of everolimus in heart transplantation. Nephrol Dial Transplant 2006; 21 (Suppl 3): iii9-13.
109. Osto E, Tona F, Castellani C, et al. Everolimus prevents the development of microvasculopathy after heart transplantation. Eur Heart J 2008; 29 (Suppl I): 52.