section name header

Info


A. Indicationsnavigator

  1. Cardiomyopathy
    1. Idiopathic Dilated Cardiomyopathy - most common
    2. Hypertrophic (obstructive) Cardiomyopathy
    3. Infiltrative and Restrictive Disease
    4. Pediatric (~25% of transplants): congenital disorders and dilative cardiomyopathy
  2. Severe Congestive Heart Failure (CHF)
    1. Post-myocardial infarction
    2. Post-myocarditis (usually dilated cardiomyopathy)
    3. Idiopathic
    4. Severe valvular disease
    5. About 250,000 persons in USA die each year from severe (Class III/IV) CHF
  3. Related to Congenital Abnormalities
  4. Approximately 3500 heart transplants per year worldwide (2500 in USA)
  5. Lack of donor organs is the main reason for so few transplants
  6. ABO incompatibile transplants are possible in infants [21]
  7. Recipient cells migrate into and function in donor hearts [24]
  8. Successful cardiac transplantation in advanced HIV-1 infected patient reported [15]
  9. Bridge to Transplantation
    1. Many patients on waiting list for transplant cannot be stabilized medically
    2. Severe left ventricular (LV) or biventricular failure indication for bridge
    3. Left ventricular assist devices (LVAD) increasingly used prior to transplantation [2]
    4. Permanent implantation of artificial heart (Jarvik 2000) may be bridge to transplant [10]
    5. Total artificial heart (CardioWest) well tolerated and superior to standard care [5]
  10. Main problem with artificial pump devices is formation of clots, subsequent embolic disease

B. Inudction (Preparative) Regimen navigator

  1. Standard Therapy
    1. Glucocorticoids (falling out of favor)
    2. Cyclosporine A (CsA) or Tacrolimus
    3. Anti-lymphocyte monoclonal antibodies increasingly used
    4. Mycophenolate mofetil increasingly replacing azathioprine
  2. Monoclonal Antibodies (MAb)
    1. Specific anti-lymphocyte reagents are being used more frequently
    2. Anti-CD3 (OKT3) mAb against T cells or polyclonal antithymocyte globulin OR
    3. Anti-IL2-Receptor MAb daclizumab (Zenapax®) has also been evaluated
    4. Daclizumab given during the three month induction period following transplant reduced incidence of acute rejection 75% (from 63% to 18%) [19]
    5. Daclizumab reduced acute cellular rejection but increased death in cardiac transplant when used with CsA, glucocorticoids and mycophenolate [28]
    6. Alemtuzumab (Campath 1H) anti-CD52 mAb depletes B, T and NK cells has also been used
    7. Acute cellular rejection episodes can be managed and do not appear to corelate with outcomes in cardiac transplant [29]
  3. Photopheresis [17]
    1. Directed at suppressing donor-specific T cell clones in recipient of graft
    2. Peripheral blood is removed and leukocyte poor fraction returned to recipient
    3. Leukocyte-enriched blood is exposed to UV light in presence of methoxsalen
    4. Methoxsalen covalently binds to DNA pyrimdines and other molecules
    5. Exposure of methoxsalen treated dividing cells to UV light causes cell death
    6. Treated leukocyte fraction returned to patient
    7. These treated leukocytes induce an autologous suppressor response mediated by T cells
    8. T suppressor cells target non-exposed T cells of similar immune specificity
    9. Thus, significant and long term graft specific T cell depletion or suppression occurs
    10. Photopheresis + triple drug immunosuppression reduced acute cardiac allograft rejection
  4. Patients should be evaluated for osteopenia prior to transplant [3]
    1. Calcitriol or alendronate (Fosamax®) prevent post-transplant bone loss
    2. Hypercalemia more common with calcitriol (27%) versus alendronate (7%)
    3. Alendronate 10mg po qd for 21 days after transplant reduces bone loss
  5. Use of LVAD improves preoperative condition and post-transplant outcomes [2]

C. Maintenance Immunosuppressionnavigator

  1. Combination Therapy Usually Used
    1. Ciclosporine or tacrolimus
    2. Azathiprine or mycophenolate or sirolimus/everolimus
    3. Glucocorticoids may be used initially, with push to taper off
  2. More than 60% of patients can be weaned completely off of glucocorticoids
  3. Cyclosporine (CsA)
    1. Effective but expensive compound with low oral bioavailability
    2. Neoral® is a CsA microemulsion formulation with improved absorption
    3. Ketoconazole reduces dose of CsA needed by slowing its metabolism
    4. Diltiazem also interferes with CsA metabolism and reduces artery spasms
    5. CsA is usually combined with azathioprine for general maintenance
  4. Chronic, low level rejection continues to occur on current regimens
    1. This can be monitored by endomyocardial biopsy
    2. Atherosclerosis is accelerated by rejection episodes
    3. Allograft coronary artery disease is a major problem (see below)
  5. Side Effects
    1. Infectious Complications
    2. Increased risk of lymphoma, particularly in first year of cyclosporine therapy
  6. Anti-lymphocyte antibodies are reserved for glucocorticoid resistant rejection

D. Infectious Complications navigator

  1. Cytomegalovirus (CMV) is a major problem
    1. Prophylaxis with gancyclovir helps prevents disease in some transplant patients
    2. This virus also increases atherosclerosis in allograft coronary arteries
  2. Other Infections include herpes zoster, pneumocystis, fungemia, bacteremia
  3. Post-Transplant Lymphoproliferative Disease (PTLD) [16]
    1. Increased risk of non-Hodgkin's lymphomas and other B-cell malignancies
    2. These are nearly all associated with Epstein-Barr virus (EBV) infection
    3. Develops in ~5% of pediatric heart transplant cases [1]
    4. Multiagent chemotherapy, radiation ± antiviral agents have been used
    5. Usually requires reduction in immunosuppressive therapy
  4. Hepatitis C virus (HCV) seropositive donor organs associated with reduced survival compared with HCV negative donors [4]
  5. Children transplanted before age 4 respond poorly to pneumococcal vaccine [11]

E. Graft Coronary Artery Disease (CAD) [1,6] navigator

  1. CAD in heart transplant patients is leading cause of graft failure after 1 year survival
    1. Patients should be evaluated about once a year
    2. Incidence of significant graft CAD is ~10% at year 1, 50% at year 5
    3. Elevated serum C-reactive protein (CRP) identifies patients at risk for graft CAD [26]
  2. Clinical risk factors for transplant atherosclerosis:
    1. Glucocorticoid use
    2. Adenovirus DNA - 4.7X increased risk for graft loss in PCR+ versus PCR- [22]
    3. Number of rejection episodes
  3. Molecular risk factors for transplant atherosclerosis
    1. Depletion of arteriolar tissue plaminogen activator (TPA) correlates with CAD [7]
    2. Incredased graft arterial ICAM-1 correlates with elevated serum CRP levels [26]
    3. Elevated CRP associated with development, severity, progression of graft CAD [26]
    4. Strongly suggests that activation (inflammation) of graft endothelium plays a major role
    5. Myocardial fibrin deposition predicts subsequent CAD [14]
  4. Rejection and CAD
    1. Strong correlation between rejection episodes and development of transplant CAD [12]
    2. HLA-DR matches reduce risk of rejection and CAD development
    3. Increased rejection and CAD with anti-HLA Class II Abs or anti-donor lymphocyte proliferation in patients with no HLA-DR matches [13]
    4. Even with low grade endomyocardial biopsy results, presence of immune responses to donor tissues predicts long term rejection and CAD [13]
    5. Adenovirus infection may stimulate immunologic rejection of cardiac graft [22]
  5. Everolimus [20]
    1. Novel proliferation inhibitor / immunosuppressant similar to sirolimus (Rapamune®)
    2. Superior to azathioprine for reducing severity and incidence of cardiac allograft CAD
    3. Combined with CsA, also reduced risk of rejection
    4. Everolimus + CsA reduced incidence of rejection and CMV infection in kidney allograft
  6. Stains for Allograft CAD [8,9]
    1. HMG-CoA reductase Inhibitors are very effective
    2. Reduced episodes of hemodynamic compromise due to rejection
    3. Reduced cholesterol levels and CAD
    4. Improved one year survival
    5. Likely reduces inflammation (CRP) levels as well as cholesterol
    6. Pravastatin, simvastatin, fluvastatin have been used
  7. Combined vitamins E (400IU bid) and C (500mg bid) prevented coronary intimal thickening in first year after transplant [25]
  8. Pain with myocardial ischemia and infarction is unusual in transplant patients
  9. Blockade of inflammatory signals has prevented CAD in animal cardiac transplantation [1]

F. Prognosisnavigator

  1. Graft Survival in Adults
    1. Year 1: 85%
    2. Year 5: 71%
    3. Year 10: 46%
  2. Patients with one or more HLA-DR matches do better than those without matches [13]
  3. Exercise rehabilitation after transplantation improves capacity for physical work [18]
  4. Sympathetic Reinnervation [23]
    1. Occurs in ~50% of patients
    2. Mainly in anteroseptal wall
    3. Associated with improved heart rate and contractile responses
    4. Reinnvervated hearts had similar response to exercise as normal controls

Resources navigator

calcCardiac Output (Fick)

References navigator

  1. Webber SA, McCurry K, Zeevi A. 2006. Lancet. 368(9529):53 abstract
  2. Goldstein DJ, Oz MC, Rose EA. 1998. NEJM. 339(21):1522 abstract
  3. Shane E, Addesso V, Namerow PB, et al. 2004. NEJM. 350(8):767 abstract
  4. Gasink LB, Blumberg EA, Localio AR, et al. 2006. JAMA. 296(15):1843 abstract
  5. Copeland JG, Smith RG, Arabia FA, et al. 2004. NEJM. 351(9):859 abstract
  6. Jarcho JA and Mark EJ. 1998. NEJM. 338(22):1608 (Case Record)
  7. Labarrere CA, Pitts D, Nelson DR, Faulk WP. 1995. NEJM. 333(17):1111 abstract
  8. Kobashigawa JA, Katznelson S, Laks H, et al. 1995. NEJM. 333(10):621 abstract
  9. Loh E, Couch FJ, Hendrickson C, et al. 1997. JAMA. 277(2):133 abstract
  10. Westaby S, Banning AP, Jarvik R, et al. 2000. Lancet. 356(9233):900 abstract
  11. Gennery AR, Cant AJ, Spickett GP, et al. 1998. Lancet. 351(9118):1778 abstract
  12. Hosenpud JF, Novick RJ, Bennett LE, et al. 1996. J Heart Lung Transplant. 15:655
  13. Itescu S, Tung TCM, Burke EM, et al. 1998. Lancet. 352(9124):263 abstract
  14. Labarrere CA, Nelson DR, Faulk WP. 1998. Am J Med. 105(9):207
  15. Calabrese LH, Albrecht M, Young J, et al. 2003. NEJM. 348(23):2323 abstract
  16. Webber SA, Naftel DC, Fricker FJ, et al. 2006. Lancet. 367(9506):232 abstract
  17. Barr ML, Meiser BM, Eisen HJ, et al. 1998. NEJM. 339(24):1744 abstract
  18. Kobashigawa JA, Leaf DA, Lee N, et al. 1999. NEJM. 340(4):273
  19. Beniaminovitz A, Itescu S, Lietz K, et al. 2000. NEJM. 342(9):613 abstract
  20. Eisen HJ, Tuzcu EM, Dorent R, et al. 2003. NEJM. 349(9):847 abstract
  21. West LJ, Pollock-Barziv SM, Dipchand AI, et al. 2001. NEJM. 344(11):793 abstract
  22. Shirali GS, Ni J, Chinnock RE, et al. 2001. NEJM. 344(20):1498 abstract
  23. Bengel FM, Ueberfuhr P, Schiepel N, et al. 2001. NEJM. 345(1):731
  24. Quaini F, Urbanek K, Beltrami AP, et al. 2002. NEJM. 346(1):5 abstract
  25. Fang JC, Kinlay S, Beltrame J, et al. 2002. Lancet. 359(9312):1108 abstract
  26. Labarrere CA, Lee JB, Nelson DR, et al. 2002. Lancet. 360(9344):1462 abstract
  27. Sayegh MH and Carpenter CB. 2004. NEJM. 351(26):2761 abstract
  28. Hershberger RE, Starling RC, Eisen HJ, et al. 2005. NEJM. 352(26):2705 abstract
  29. Hosenpud JD. 2005. NEJM. 352(26):2749 abstract