Basics
Description
- Cardiac transplantation is a well-established therapeutic option for end-stage heart disease in selected patients. It offers prolonged life and improved quality-of-life, but carries with it the long-term consequences of chronic immunosuppressive therapy.
- Indications for transplant (any 1 of the following):
- New York Heart Association Class III or IV heart failure symptoms with peak oxygen consumption ≤10 mL/kg/min (≤14 mL/kg/min in the case of severe symptoms), despite optimal medical therapy and cardiac resynchronization therapy (if appropriate). Medically induced causes (eg, hypothyroidism, tachycardia, obstructive sleep apnea, alcohol or cocaine abuse, HTN, medication noncompliance) and surgically correctible causes (eg, valvular dysfunction, coronary artery disease, hypertrophic cardiomyopathy, LV aneurysm) must be excluded
- Cardiogenic shock requiring mechanical support (ventricular assist device or intra-aortic balloon pump)
- Recurrent life-threatening ventricular arrhythmia refractory to anti-arrhythmic medications, ablation, and ICD
- Refractory angina without medical, interventional, or surgical options
- End-stage congenital heart disease without pulmonary HTN
- United Network for Organ Sharing (UNOS) listing criteria:
- Status 1A: Inpatients, life expectancy <7 days, mechanical assist device (for <30 days), complication with mechanical assist device (eg, infection, thrombus), high-dose, Swan-Ganz catheter-guided inotropic therapy.
- Status 1B: Inotrope-dependent, ventricular assist device for >30 days.
- Status 2: Not inotrope-dependent.
- Status 7: Inactive list, due to temporary improvement or contraindication to surgery.
Epidemiology
- ~3,000 patients on the UNOS waiting list for heart transplantation; current waiting list can be obtained by visiting the UNOS website (www.unos.org)
- Percentage of patients on UNOS waiting list who underwent transplant in 2003-2004: 90% of Status 1A patients; 89% of Status 1B; 65% of Status 2 patients.
- National median waiting time for heart transplant (2003-2004): 49 days for Status 1A; 77 days for Status 1B; 308 days for Status 2. Waiting times vary by blood type, with Type O having the longest waiting time.
- Reported number of heart transplants performed in 2005 worldwide: 3,095 (steadily decreasing from peak 4,439 transplants in 1994- probably due to under-reporting as well as decreased volume).
- Average recipient age ( �SD) worldwide (2004-2006): 51( �13) yr old; range 18-77 yr old; 25% were >60 yr old.
- Average donor age ( �SD) worldwide (2004-2006): 34( �13) yr old; range 9-67 yr old.
Risk Factors
Contraindications to heart transplantation: Active infection; active malignancy other than skin cancer; severe irreversible lung, liver, or kidney disease (unless combined heart-lung, heart-liver, or heart-kidney transplant is indicated); recent pulmonary embolism; severe peripheral vascular or cerebrovascular disease; severe diabetes with end-organ damage; severe osteoporosis; severe obesity; substance abuse or other psychosocial instability �
Has been successful in patients who have undergone heart transplantation. �
Pathophysiology
The transplanted heart is denervated, resulting in the following phenomena: �
- Heart rate does not rise acutely in response to exertion, but does demonstrate a delayed rise in response to circulating catecholamines.
- Transplant recipients who develop significant cardiac allograft vasculopathy (CAV) or traditional atherosclerotic CAD may not have typical anginal symptoms in the setting of ischemia.
- Reinnervation may occur over time in some transplant recipients.
Etiology
Primary indications for transplant worldwide: Coronary heart disease (41%) and nonischemic cardiomyopathy (45%). �
Associated Conditions
- Immunosuppressive therapy predisposes patients to various infections, cancers, HTN, renal insufficiency, hyperlipidemia, diabetes, osteoporosis.
- CAV: Progressive neointimal proliferation resulting in diffuse coronary luminal narrowing; it accounts for 30% of mortality 5 yr post transplant; may be clinically silent due to denervation of heart; routine surveillance with angiography and IVUS is recommended; treatment is difficult; usually requires intensification of immunosuppression (TOR inhibitors may be useful).
Diagnosis
Tests
Lab
Lab
Prior to transplant: �
- CBC, metabolic panel, thyroid and liver function tests, lipids, HLA typing, panel of reactive antibody screen, serology for various infections (HIV, hepatitis, herpes, CMV, toxoplasmosis, varicella, rubella, EBV, syphilis), cancer screening ( PSA, PAP smear), colonoscopy, bone density scan, carotid Doppler, ABIs.
- Cardiopulmonary exercise testing: To be eligible for transplant for CHF, patient must have a peak oxygen consumption (Vo2) <10 mL/kg/min; or peak Vo2 ≤14 mL/kg/min (≤12 mL/kg/min on β-blocker) plus major limitation in activities of daily living (ADL) may also be accepted. β-Blockers and ICDs improve survival without changing peak Vo2; CRT improves survival and also increases peak Vo2.
- Right heart catheterization: Measurement of PVR is required, as up to 20% of early deaths after cardiac transplant are due to RV failure from pulmonary HTN. Goal PVR is <200 dynes/sec/cm5 (<4.0 Wood Units), on vasodilators or ventricular assist device if needed.
- Echo: LV ejection fraction is not a reliable indicator of need for transplant.
LabFollowup
Post transplant: �
- Endomyocardial biopsy: Should be performed weekly/biweekly for the 1st few months, and then at gradually increasing intervals over the next 3-4 yr to assess for graft rejection
- Gene expression profiling: New modality (available since 2005); non-invasive and less expensive than endomyocardial biopsy for surveillance of graft rejection. It is still being studied, but may be used in clinically stable adults >6 mo post transplant.
- Coronary angiography: Should be performed routinely to assess for coronary allograft vasculopathy.
- Echo: May show dual sinus node activity (from donor and recipient atria)
Pathological Findings
Grading System for graft rejection: Grade 0 = normal; Grade 1R = mild; 2R = moderate; 3R = severe cellular rejection on endomyocardial biopsy. �
Treatment
Medication
- Immunosuppressants: Standard triple therapy usually includes a calcineurin inhibitor, an antiproliferative agent (eg, mycophenolate mofetil or azathioprine), and a corticosteroid (steroid is usually weaned off):
- Calcineurin inhibitors:
- Cyclosporine: Narrow therapeutic window; dosed by trough levels; side effects include nephrotoxicity, HTN, hirsutism, gingival hyperplasia, and tremor.
- Tacrolimus: Sometimes 1st-line agent in female patients since cyclosporine causes hirsutism; dosed by serum levels; side effects include nephrotoxicity and neurotoxicity (most commonly tremor).
- Mycophenolate mofetil: Preferred over azathioprine due to improved mortality (6.2% vs. 11.4% at 1 yr; p = 0.03) and reduced graft rejection; however the price is almost 10-fold higher; may be dosed by levels of mycophenolic acid (active metabolite); side effects include GI symptoms and myelosuppression.
- Azathioprine: Typically the 2nd-line agent if mycophenolate mofetil is not tolerated; no serum assay available; side effects include myelosuppression.
- Steroids: Prednisone or Solu-Medrol for chronic immunosuppression or acute rejection; usually weaned off; side effects include diabetes, HTN, osteoporosis (femoral head avascular necrosis).
- TOR inhibitors (inhibitors of the target of rapamycin enzyme): Sirolimus and everolimus; have a synergistic effect when combined with calcineurin inhibitors, or may be used in place of calcineurin inhibitors in the case of renal dysfunction; inhibit vascular smooth muscle cell growth and proliferation, reducing CAV; side effects include hypertriglyceridemia, thrombocytopenia, and impaired wound healing.
- Induction therapy and therapy for steroid-resistant acute rejection: Induction therapy is indicated immediately after transplant, most commonly in patients with contraindication to calcineurin inhibitors due to severe renal dysfunction. Choices include: OKT3 (Muromonab-CD3), polyclonal antilymphocyte antibodies, and IL-2 receptor blockers (basiliximab, daclizumab).
- Antihypertensives: Calcium channel blockers (especially diltiazem) decrease hepatic metabolism of cyclosporine and are sometimes added to reduce cyclosporine dose requirement.
- HMG-CoA reductase inhibitors: Use caution due to increased risk of rhabdomyolysis with concomitant cyclosporine.
- For Pneumocystis carinii (trimethoprim-sulfamethoxazole); may be stopped once patient is on a stable immunosuppression regimen. Prophylactic regimen for positive CMV serology is also indicated (ganciclovir).
- Bisphosphonates, calcium, vitamin D: For osteoporosis secondary to steroids.
Surgery
- Orthotopic transplant: Donor heart is implanted in place of native heart:
- Biatrial (lower-Shumway) method: The donor atria are attached directly to the native atria. Disadvantage of this technique is disruption of normal atrial geometry, resulting in sinus node dysfunction.
- Bicaval method: The superior and inferior vena cava are attached separately, leaving the donor right atrium intact. Use of this technique has been increasing.
- Disadvantages include slightly longer ischemic time and potential SVC stenosis.
- Advantages include less atrial arrhythmia.
- Combined heart and lung transplant may be considered for patients with severe fixed pulmonary HTN. Combined heart-liver or heart-kidney transplant may also be considered if indicated.
- Ventricular assist device (VAD) may be required as bridge to heart transplant.
- Cardiac resynchronization therapy (CRT) may improve functional status and preclude transplant.
- ICD may be indicated for primary or secondary prevention.
- Retransplantation may be considered for graft failure, but mortality is higher.
Ongoing Care
Follow-Up Recommendations
Patient Monitoring
- Routine cardiac surveillance as noted above
- Routine cancer screening
Patient Education
Visit website for United Network for Organ Sharing: www.unos.org �
Prognosis
- 1-yr survival rate is 84%.
- Median survival post transplant is 10 yr; 13 yr for those who survive the 1st yr.
- Between 1982 and 2005, survival for adult transplant recipients has improved.
- Cause of death:
- 1-30 days post transplant: Graft failure (40%), multiorgan failure (14%), non-CMV infection (13%)
- 1-12 mo post transplant: Non-CMV infection (33%), graft failure (18%), acute graft rejection (12%)
- ≥5 yr post transplant: CAV and late graft failure (likely due to CAV) (33%), malignancy (22%), non-CMV infection (10%)
Complications
- Postoperative: Pericardial effusion is common, but tamponade develops rarely. LV systolic and diastolic dysfunction due to ischemia-reperfusion, usually resolves over days to weeks.
- RV dysfunction is more common than LV dysfunction, due to elevated pulmonary artery pressures.
- Sinus node dysfunction and other atrial arrhythmias: Temporary atrioventricular pacing is often required.
- Renal dysfunction due to calcineurin inhibitors and/or hypoperfusion.
- Hyperacute graft rejection, due to preformed antibodies, can occur immediately and is usually fatal.
- Graft rejection: Either cellular rejection, which is lymphocyte-mediated; or vascular (humoral) rejection, which is antibody-mediated.
- CAV
- Malignancy: Lung, colon, breast, skin cancer (skin cancer particularly common with azathioprine); post transplant lymphoproliferative disease (PTLD) due to Epstein-Barr virus; cervical cancer related to HPV. Cancer risk increases with cumulative immunosuppression; history of induction therapy increases risk.
- Infections: CMV, Pneumocystis carinii (jiroveci) pneumonia, other.
- HTN: Due to calcineurin inhibitors and steroids.
- Renal failure: Due to calcineurin inhibitors
- Osteoporosis, adrenal insufficiency, and diabetes: Due to chronic steroid use; risk of femoral head avascular necrosis.
Additional Reading
1
Abrahams �Z, Mullens �W, Boyle �A.
Cardiac Transplantation. In: Griffin �BP, Topol �EJManual of cardiovascular medicine, 3rd ed.Philadelphia: Lippincott Williams & Wilkins, 2009;171-190. 2
Jessup �M, Banner �N. Optimal pharmacologic and non-pharmacologic management of cardiac transplant candidates: Approaches to be considered prior to transplant evaluation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates-2006. J Heart Lung Transplant. 2006;25(9):1003-1023. �[View Abstract] 3
Mehra �MR, Kobashigawa �J. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates-2006. J Heart Lung Transplant. 2006;25(9):1024-1042. �[View Abstract] 4
Taylor �DO, Edwards �LB. Registry of the International Society for Heart and Lung Transplantation: Twenty-fourth official adult heart transplant report-2007. J Heart Lung Transplant. 2007;26(8):769-781. �[View Abstract]
Codes
ICD9
- V42.1 Heart replaced by transplant
- 428.9 Heart failure, unspecified
- 996.83 Complications of transplanted heart
SNOMED
- 84114007 heart failure (disorder)
- 429257001 disorder of transplanted heart (disorder)
- 233932001 cardiac transplant disorder (disorder)
Clinical Pearls
- Indications for transplant include refractory heart failure, refractory angina, refractory ventricular arrhythmia, cardiogenic shock, and end-stage congenital heart disease without pulmonary HTN.
- Active malignancy, severe diabetes, severe peripheral vascular disease, and psychosocial instability are contraindications to transplant.
- Metabolic exercise test for peak Vo2 (≤10-14 mL/kg/min) and right-heart catheterization for PVR (<4.0 Wood Units) are key factors in predicting benefit and success of heart transplant.
- 1-yr survival post-transplant is 84%, and median survival is 10 yr.
- Common causes of death are cardiac allograft vasculopathy, cancer, and infections.