Cardiac allograft vasculopathy prevention

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2] Raviteja Guddeti, M.B.B.S. [3]

Overview

Prevention

As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal immunosuppressive therapy. However, the best preventative strategy to delay development of CAV is yet to be determined.

Optimization of Immunosuppressive Therapy

The rapamycin derivatives, sirolimus and everolimus, have been proven to have significant benefit in the prevention of CAV in addition to statins. Other options for immunosuppressive therapy include [1]:

Everolimus and Sirolimus

  • Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
  • Everolimus is currently not FDA approved for clinical use in the United States.
  • Associated with significantly reduced incidence of graft rejection.
  • Serial IVUS studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking everolimus [2]. Similar results were found in trials that studied sirolimus [3].
  • Side effect profile:

Mycophenolate mofetil

Calcineurin inhibitors

Non-Immunosuppressive therapy

Non-immunosuppressive therapy includes:

Statins

  • Obesity, elevated levels of cyclosporine, use of steroids and insulin resistance all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
  • Immunomodulatory effects of statins include:
    • Inhibition of smooth muscle proliferation
      • By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
      • By inhibiting expression of genes for growth factors essential for proliferation of smooth muscles
    • Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against atherogenesis.
    • Prevents attachment of monocytes to endothelium, which is the first step in atherogenesis [5]
    • In the presence of immunosuppressants like cyclosporin A, statins reduce natural killer cell activity, T cell proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A [6].
  • Long term effects of simvastatin: The effects of simvastatin over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues [5] in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
    • At the end of 8 years, the Kaplan-Meier survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
  • Long term effects of pravastatin: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of pravastatin at one year [7] and at the end of ten years [8].
    • After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
    • These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

Calcium Channel Blockers and ACE inhibitors

  • Mechanisms by which calcium channel blockers (CCB's) and ACE inhibitors are thought to prevent CAV are as follows [9]:
    • Preservation of endothelial function
    • Reduced oxidative stress
    • Suppression of smooth muscle cell migration and proliferation
    • Additionally nifedipine has been shown to cause vasodilatation in coronary arteries with endothelial dysfunction and inhibition of endothelin production [10].
  • In a study by Schroeder and colleagues[11] involving 57 cardiac transplant patients randomized to either receive diltiazem or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up. However the overall survival at the end of 2 years remained unchanged.
  • Synergistic effect of CCBs and ACE inhibitors: This was suggested by Erinc et al. when their study involving 82 heart transplant patients showed that combined use of CCB's and ACE inhibitors was associated with improvement in IVUS indices of CAV. These patients were randomized to receive either calcium channel blockers or ACE inhibitors or both or placebo and followed for one year.
  • However, longer term trials are required to prove the effects of CCBs and ACE inhibitors on survival and mortality.

Anti-cytomegalovirus Therapy

  • Cytomegalovirus (CMV), the most common infection encountered in cardiac transplant patients, may be subclinical and causes acceleration of CAV development by the following mechanisms:
  • Simialr to CMV, adenovirus, parvovirus and Chlamydiae pneumoniae is thought to trigger development of CAV [12].
  • Gancicylcovir appears to slow the progression of CAV. Also early control of subclinical CMV infections may limit rejection and prevent CAV [13].

Antioxidants

  • Mechanism of antioxidants in prevention of CAV involved:
    • Augmenting endothelial nitric oxide (NO) activity
    • Inhibiting the deleterious effects of free oxygen radicals on nitric oxide synthesis thereby preventing endothelial dysfunction and development of CAV
  • Vitamin C & E, L-arginine and tetrahydrobiopterin supplementation can theoretically be beneficial, however long term trials to establish the effects of these agents in improving survival are lacking [9].

References

  1. Mehra MR (2006). "Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy". Am J Transplant. 6 (6): 1248–56. doi:10.1111/j.1600-6143.2006.01314.x. PMID 16686747.
  2. Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA; et al. (2003). "Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients". N Engl J Med. 349 (9): 847–58. doi:10.1056/NEJMoa022171. PMID 12944570.
  3. Matsuo Y, Cassar A, Yoshino S, Flammer AJ, Li J, Gulati R; et al. (2013). "Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation". J Heart Lung Transplant. 32 (8): 784–91. doi:10.1016/j.healun.2013.05.015. PMC 3727915. PMID 23856215.
  4. Eisen HJ, Kobashigawa J, Keogh A, Bourge R, Renlund D, Mentzer R; et al. (2005). "Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients". J Heart Lung Transplant. 24 (5): 517–25. doi:10.1016/j.healun.2005.02.002. PMID 15896747.
  5. 5.0 5.1 Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K; et al. (2003). "Simvastatin initiated early after heart transplantation: 8-year prospective experience". Circulation. 107 (1): 93–7. PMID 12515749.
  6. Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K (1996). "Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro". Immunopharmacology. 34 (1): 51–61. PMID 8880225.
  7. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM; et al. (1995). "Effect of pravastatin on outcomes after cardiac transplantation". N Engl J Med. 333 (10): 621–7. doi:10.1056/NEJM199509073331003. PMID 7637722.
  8. Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA; et al. (2005). "Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients". J Heart Lung Transplant. 24 (11): 1736–40. doi:10.1016/j.healun.2005.02.009. PMID 16297773.
  9. 9.0 9.1 Weis M (2002). "Cardiac allograft vasculopathy: prevention and treatment options". Transplant Proc. 34 (5): 1847–9. PMID 12176600.
  10. Weis M, Pehlivanli S, von Scheidt W (2002). "Vasodilator response to nifedipine in human coronary arteries with endothelial dysfunction". J Cardiovasc Pharmacol. 39 (2): 172–80. PMID 11791002.
  11. Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB; et al. (1993). "A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients". N Engl J Med. 328 (3): 164–70. doi:10.1056/NEJM199301213280303. PMID 8417382.
  12. Valantine HA (2003). "Cardiac allograft vasculopathy: central role of endothelial injury leading to transplant "atheroma"". Transplantation. 76 (6): 891–9. doi:10.1097/01.TP.0000080981.90718.EB. PMID 14508350.
  13. Tu W, Potena L, Stepick-Biek P, Liu L, Dionis KY, Luikart H; et al. (2006). "T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease". Circulation. 114 (15): 1608–15. doi:10.1161/CIRCULATIONAHA.105.607549. PMID 17015794.



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