Cardiac Transplantation Board Review

1. Cardiac Transplantation Board Review Brian W. Zagol, M.D. Department of Cardiology University of Tennessee

2. Introduction • More than 4000 patients in the United States are registered with the United Organ Sharing Network (UNOS) for cardiac transplantation. • There are only about 2500 heart donors yearly. • Scarcity of donors is complicated by the use of single organs, heart injury with common brain-death injuries, difficulty with ex-vivo preservation, heart disease among donors, and the complexity of the operation.

3. Class I Indications for Cardiac Transplantation • Cardiogenic shock requiring mechanical assistance. • Refractory heart failure with continuous inotropic infusion. • NYHA functional class 3 and 4 with a poor 12 month prognosis. • Progressive symptoms with maximal therapy. • Severe symptomatic hypertrophic or restrictive cardiomyopathy. • Medically refractory angina with unsuitable anatomy for revascularization. • Life-threatening ventricular arrhythmias despite aggressive medical and device interventions. • Cardiac tumors with low likelihood of metastasis. • Hypoplastic left heart and complex congenital heart disease.

4. Indications of Cardiac Transplantation • Patients should receive maximal medical therapy before being considered for transplantation. They should also be considered for alternative surgical therapies including CABG, valve repair / replacement, cardiac septalplasty, etc. • VO2 has been used as a reproducible way to evaluate potential transplant candidates and their long term risk. Generally a peak VO2 >14ml/kg/min has been considered “too well” for transplant as transplantation has not been shown to improve survival over conventional medical therapy. Peak VO2 10 to 14 ml/kg/min had some survival benefit, and peak VO2 <10 had the greatest survival benefit.

5. Contraindications to Cardiac Transplantation

6. Evaluation of Cardiac Transplantation Recipient • Right and Left Heart Catheterization. • Cardiopulmonary testing. • Labs including BMP, CBC, LFT, UA, coags, TSH, UDS, ETOH level, HIV, Hepatitis panel, PPD, CMV IgG, RPR / VDRL, PRA (panel of reactive antibodies), ABO and Rh blood type, lipids. • CXR, PFT’s including DLCO, EKG. • Substance abuse history and evidence of abstinence for at least 6 months and enrollment in formal rehabilitation. • Mental health evaluation including substance abuse hx and social support. • Financial support. • Weight no more than 140% of ideal body weight.

7. Status Listing • Once accepted as a transplant candidate, a patient is entered on the list and given a status based upon severity of illness. • If status changes, time accrual starts over. Status I heart recipients are given preference over status I heart / lung recipients who are given preference over status II heart recipients. • Zones are established to give local priority to recipients within 500 to 1000 mile radius centered on donor site.

8. Status Listings • Status I. • Cardiac Assistance • Total artificial heart • Ventricular assist devices • Intraaotic balloon pump • Ventilator • Inotrope dependent for maintaining cardiac output and in hospital intensive care unit • Younger than 6 months • Status II. Patients not status I according to criteria • Status VII. Patients improved and not in immediate need of transplantation or with new complication making transplantation contraindicated.

9. Cardiac Donor • Brain death is necessary for any cadaveric organ donation. This is defined as absent cerebral function and brainstem reflexes with apnea during hypercapnea in the absence of any central nervous system depression. • There should be no hypothermia, hypotension, metabolic abnormalities, or drug intoxication. • If brain death is uncertain, confirmation tests using EEG, cerebral flow imaging, or cerebral angiography are indicated.

10. Cardiac Donor – Exclusion Criteria • Age older than 55 years. • Serologic results (+) for HIV, Hepatitis B or C. • Systemic Infection. • Malignant tumors with metastatic potential (except primary brain tumors) • Systemic comorbidity (diabetes mellitus, collagen vascular disease) • Cardiac disease or trauma • Coronary artery disease • Allograft ischemic time estimated to be > than 4-5 hours • LVH or LV dysfunction on echocardiography • Death of carbon monoxide poisoning • IV drug abuse.

11. Care of Donor Before Transplantation • Contact local organ procurement organization (OPO). • Obtain patient’s height and weight. • Collect CBC, CMP, ABO / Rh testing, HIV, Hepatitis panel, and CMV Ab. • EKG. • Echocardiogram. (Fellow should be paid for this, especially if after hours) • Consider cardiac catheterization if man over 40-45 or woman over 45-50. • Insert arterial line and right heart catheter.

12. Care of Donor Before Transplantation • Donors with beating hearts are often volume depleted because of therapy directed at reducing cerebral edema. • As soon as consent for organ transplantation is obtained (usually by OPO), normal saline should be started or sparingly blood. • A goal CVP should be 5 to 10 and PCWP of 10 to 16. • Arterial systolic BP should be maintained at least 100mmHg. If CVP and PCWP are adequate and hypotension persists dopamine and / or dobutamine should be initiated.

13. Care of Donor Before Transplantation • Diabetes Insipidus should be suspected if urine output is >300cc/hr or if hypernatremia begins to develop. Vasopressin and hypotonic solutions can be used in this setting. • Electrolytes should be measured and corrected hourly until organ procurement. Hypertension as a result of sympathetic discharge can be managed with IV NTG. • Hyperpyrexia or hypothermia should be addressed with surveillance cultures, empiric broad-spectrum antibiotics, cooling / warming blankets.

14. Care of Donor Before Transplantation • Metabolic acidosis from loss of adrenal and thyroid hormone secretion of brain death can depress myocardial contractility and cause vasodilatation. Acidosis should be corrected. • Ventricular dysfunction sometimes responds to levothyroxine 4 micrograms/kg/hr and methylprednisolone 100mg IV qhr and can be tried in this situation. Some recommend empiric treatment with these agents.

15. Care of Donor Before Transplantation • Echo should be performed as soon as possible on the donor heart for assessment of LV function. If unexpected dysfunction is found in a young person, LVEDD and wall thickness should be measured. If dimensions are normal then corticosteroid and thyroid replacement should begin and any acidosis should be corrected. • Particular attention should be paid to wall motion abnormalities (especially in individuals with more advanced age), aortic stenosis, and significant mitral valve abnormalities.

16. Care of Donor Before Transplantation • Coronary angiography should be performed on men older than 45 and women older than 50. • Precise definition of coronary anatomy is not the goal! Quick exclusion of severe lesions is! • The sheath should be sutured in place for ICU monitoring and blood sampling. Removal may also be complicated by coagulopathy. • Risk to potential donor kidneys necessitates limiting contrast exposure. Use non-ionic contrast and <25cc’s if possible. No LVgram unless absolutely necessary.

17. Matching Donor and Recipient • Because ischemic time during cardiac transplantation is crucial, donor recipient matching is based primarily not on HLA typing but on the severity of illness, ABO blood type (match or compatible), response to PRA, donor weight to recipient ratio (must be 75% to 125%), geographic location relative to donor, and length of time at current status. • The PRA is a rapid measurement of preformed reactive anti-HLA antibodies in the transplant recipient. In general PRA < 10 to 20% then no cross-match is necessary. If PRA is > 20% then a T and B-cell cross-match should be performed. • Patients with elevated PRA will need plasmapheresis, immunoglobulins, or immunosuppresive agents to lower PRA.

18. Surgical Transplantation Techniques • Orthotopic implantation is the most common – it involves complete explantation of the native heart. • Biatrial anastomosis: Most common because the ischemic time is shorter. Complications include atrial dysfunction due to size mismatch of atrial remnants and arrhythmia (sinus node dysfunction, bradyarrhythmias, and AV conduction disturbances) that necessitate PPM implantation in 10-20% of patients. • Bicaval anastomosis: Decreases incidence of arrhythmias, the need for a pacemaker, and risk for mitral or tricuspid regurgitation. However narrowing of the SVC and IVC make biopsy surveillance difficult and ischemic times can be prolonged.

19. Surgical Transplantation Techniques • Heterotopic implantation is an alternative technique in which the donor heart functions in parallel with the recipient’s heart. • It accounts of less than 0.3% of heart transplants. • This procedure can be considered if the donor heart is small enough to fit into the mediastinum without physical restriction of function. • Hypertopic transplantation is beneficial if the patient : • Has pulmonary hypertension that would exclude orthotopic transplantation. • Has heart failure that is potentially reversible (myocarditis) allowing future removal of the transplant. • The negative aspects of this approach include: • A difficult operation. • No anginal relief. • Need for anticoagulation (the native heart can cease to function and thrombose). • Contraindicated if the native heart has significant tricuspid or mitral regurgitation.

20. Physiologic concerns of Transplant • Biatrial connection means less atrial contribution to stroke volume. • Resting heart rate is faster (95 to 110 bpm) and acceleration of heart rate is slower during exercise because of denervation. • Diurnal changes in blood pressure are abolished. • Diastolic dysfunction is very common because the myocardium is stiff from some degree of rejection and possibly from denervation.

21. Postoperative Complications • Surgical • Aortic pseudoaneurism or rupture at cannulation site • Hemorrhagic pericardial effusion due to bleeding or coagulopathy • Medical • Severe tricuspid regurgitation • RV failure • Pulmonary artery compression • Pulmonary hypertension • LV failure • Ischemia • Operative Injury • Acute rejection

22. Postoperative Complications • Rhythm disturbances • Asystole • Complete heart block. • Sinus node dysfunction with bradyarrhythmias (25% permanent but most resolve within 1-2 weeks). • Atrial fibrillation. • Ventricular tachycardia. • Coagulopathy induced by cardiopulmonary bypass • Respiratory failure • Cardiogenic pulmonary edema. • Noncardiogenic pulmonary edema. • Infection. • Renal or hepatic insufficiency • Drugs. • CHF.

23. Treatment of Postoperative Complications • Treatment is directed at maintaining organ perfusion, oxygenation, acid-base balance, avoiding RV failure, and managing arrhythmias. • If needed drugs to maintain perfusion include dopamine, milrinone, NTG, Nitroprusside, isoproterenonol. • Managing RV failure is difficult. • Improve hypoxemia, acidosis, uremia, and electrolyte imbalance. • Keep transpulmonary gradient <10mmHg and PVR < 6 woods units • If vasodilators, volume reduction with diuretics and ultrafiltration, and inotropic agents fail to improve RV function, then RVAD can be considered.

24. Treatment of Postoperative Complications • Arrhythmias – may signify acute rejection. • Bradyarrhythmias • Isoproterenol 0.01 to 0.02 micrograms/kg/min. • AV sequetial pacing. • Most resolve in 1 to 2 weeks. • AV disturbances in the early postoperative period may indicate incomplete myocardial preservation, pulmonary hypertension, acute rejection, or cardiac edema. • Tachyarrhythmias • Amiodarone, Lidocaine, B-blockers, etc.

25. Postoperative Management • Initiation of medications, particularly immunosuppressive agents begins on the day of the operation. • Cyclosporin started IV on day of the surgery and usually continued until day 3 at which time converted to po. Usual IV dose is 0.5 mg/kg at 2 mg/min qd • Azathioprine 2 mg/kg IV qd until day 3 and then converted to po. • Solumedrol 125mg IV q8h until tolerating po and then Prednisone 0.6 mg/kg/day. • +/- Muromonab-CD3 (OKT3) started on postop day 1 at 5mg IV qd.

26. Postoperative Management • Pneumocystis carinii prophylaxis is started within the first week after transplant. • If patient or donor is CMV positive then ganciclovir is started on postop day 2. • Endomyocardial biopsy is performed on postop day 4 and steroids can begin to be tapered if there is no rejection greater than grade 2b. • Anticoagulation is started if heterotopic transplantation has been performed. • Amylase and lipase are measured on day 3 to detect pancreatitis. • ECG’s are obtained qday.

27. Long-term Management • Endomycardial biopsy is performed once a week for the first month and then less frequently depending on the presence or absence of rejection (usual regimen is qweek x 4 weeks, qmonth x 3 months, q3months in 1st year, q4months in 2nd year, 1 to 2 times per year subsequently). • If the donor was CMV positive a Hickman or peripherally inserted central catheter is placed for IV gangciclovir (5mg/kg IV bid x 14 days then 6mg/kg IV qd x 14 days. If the recipient was CMV negative then oral acyclovir is admisitered orally. If the recipient is CMV seropositive then the antiviral agent can be discontinued. If seroconversion occurs during treatment (and check at 1, 2, 3, and 6 month intervals), then ganciclovir is initiated for at least an additional 2 week period.

28. Long-term Management • Cyclosporine levels are checked periodically by individual center protocols. • Echocardiography is useful periodically and as an adjunct to endomyocardial biopsy. • Cardiac catheterization is performed annually for early detection of allograft vasculopathy. • There is probably no need for routine exercise or nuclear stress testing.

29. Immunosuppressive Agents • Azathioprine: purine analogue that works by nonspecific suppression of T and B-cell lymphocyte proliferation. • Dosage is 1 to 2 mg/kg per day. • Side effects are bone marrow suppression (dose related), increased incidence of skin cancer (use sunscreen), cutaneous fungal infections, and rarely liver toxicity and pancreatitis. • Drug interactions: allopurinol (decrease dose by 75%) and TMP/Sulfa (worsens thrombocytopenia).

30. Immunosuppressive Agents • Cyclosporin: inhibits T-cell lymphokine production. Highly lipophilic. • Dosage is 8 to 10mg/kg/day in 2 divided doses. IV doses are 1/3 of oral doses in a continuous infusion. • Drug levels are frequently measured for dosage and toxicity, but levels are not highly predictive of actual immunosuppressive effect. Drug levels are reflected for 5 to 10 days because of a long half life. • Side effects: nephrotoxicity caused by afferent arteriolar constriction and manifested by oliguria. Loop diuretics may exacerbate this side effect. Dosage adjustments should only be made if creatinine level is >3.0mg/dL (some renal insufficiency is expected). Other side effects include hypertension, hypertrichosis, tremor, hyperkalemia, hyperlipidemia, and hyperuricemia. • Multiple drug interactions.

31. Immunosuppressive Agents • Corticosteroids: immunosuppressives of uncertain mechanism. Used for maintenance of immunosuppression and to manage acute rejections. • High doses used initially tapered over the 1st 6 months to 5 to 15mg/d prednisone. • Side effects include mood and sleep disturbances, acne, weight gain, obesity, hypertension, osteopenia, and hyperglycemia.

32. Immunosuppressive Agents • Mycophenolate mofetil: selectively inhibits lymphocyte proliferation. • Dosage is 2g/d po. • Side effects include GI disturbances. Does not cause significant bone marrow suppression. • FK-506 (tacrolimus): Lymphophilic macrolide that inhibits lymphokine production similar to cyclosporine. • More toxic than cyclosporine. • Side effects include nephrotoxicity and neuotoxicity.

33. Immunosuppressive Agents • Antilymphocyte globulin: Horse polyclonal antibody designed to inhibit T cells by binding to surface antigens. • It is generally used at the time of transplantation for induction therapy or during acute rejections. • Dosage is 10 to 15 mg/kg qd through a central venous catheter. • Goal is to keep T lymphocyte count ~200cells/microL. • Side effects include fevers, chills, urticaria, serum sickness, and thrombocytopenia.

34. Immunosuppressive Agents • Muromonab-CD3 (OKT3): a murine monoclonal antibody to the CD3 complex on the T-cell lymphocyte designed for selective T-cell depletion. • Usual dose is 5mg/d IV bolus over 10 to 14 days. • CD3 cells are monitored with goal <25cells/mL. • Used in patients with renal insufficiency. • Side effects include cytokine release syndrome (fever, chills, nausea, vomiting, mylagia, diarrhea, weakness, bronchospasm, and hypotension), pulmonary edema. • Rapamycin: Similar mechanism of action of FK-506 except that it antagonizes the proliferation of nonimmune cells such as endothelial cells, fibroblasts, and smooth muscle cells. • Not routinely used at present. • May have a roal in prevention of immunologically mediated coronary allograft vasculopathy.

35. Basic Drug Regimen • Immunosuppressives • Antibiotic prophylaxis • PCP: TMP/Sulfa or Dapsone or Pentamidine aerosols. • CMV infection: Ganglyclovir, acyclovir. • Fungal infections: Nystatin. • Antihypertensives • Diuretics as needed • Potassium and Magnesium replacement (cyclosporin leads to wasting of thes electrolytes. • Lipid-lowering agents. (Avoid allograft vasculopathy). • Glucose lowering agents (DM and steroids) • Anticoagulation if transplant heterotopic. • Cyclosporin dose lowering meds (Diltiazem / Verapamil / Theophyilline)

36. Complications - Rejection • Avoidance with preoperative therapy with cyclosporin, corticosteroids, and azathioprine. • If rejection is suspected then workup should include: measurement of cyclosporine level CKMB level, echocardiography for LV function, and endomyocardial biopsy. • Signs and symptoms of rejection only manifest in the late stages and usually as CHF (rarely arrhythmias). Due to close surveillance, most rejection is picked up in asymptomatic patients.

37. Complications - Rejection • Hyperacute Rejection: Caused by preforemd antibodies against the donor in the recipient. It occurs within minutes to hours and is uniformly fatal. PRA screening is the best method in avoiding hyperacute rejection. • Acute Cellular Rejection: Most common form and occurs at least once in about 50% of cardiac transplant recipients. Half of all episodes occur within the first 2 to 3 months. It is rarely observed beyond 12 months unless immunosuppression has been decreased.

38. Complications - Rejection • Vascular (humoral) Rejection: not well defined. • Characterized by immunoglobulin and complement in the microvasculature with little cellular infiltrate. • It is associated with positive cross match, sensitization to OKT3, female sex, and younger recipient age. • It is more difficult to treat than acute cellular rejection, is associated with hemodynamic instability, and carries a worse prognosis.

39. Staging of Acute Rejection • If acute rejection is found, histologic review of endomyocardial biopsy is performed to determine the grade of rejection. • Grade 0 — no evidence of cellular rejection • Grade 1A — focal perivascular or interstitial infiltrate without myocyte injury. • Grade 1B — multifocal or diffuse sparse infiltrate without myocyte injury. • Grade 2 — single focus of dense infiltrate with myocyte injury. • Grade 3A — multifocal dense infiltrates with myocyte injury. • Grade 3B — diffuse, dense infiltrates with myocyte injury. • Grade 4 — diffuse and extensive polymorphous infiltrate with myocyte injury; may have hemorrhage, edema, and microvascular injury.

40. Treatment of Acute Rejection • Grade 1A and Grade 1B: No treatment is necessary. • Grade 2: Probably no treatment is necessary. Short course of steriods (Prednisone 100mg qd x 3 days) is optional. • Grade 3A and Grade 3B: High dose corticosteroids (Solumedrol 1mg/kg IV). If no response then ATGAM (OTK3 also an option, but causes more intense cytokine reaction). • Grade 3 with hemodynamic compromise or Grade 4: High dose corticosteriods plus ATGAM or OTK3. • It is critical that an endomyocardial biopsy be performed to document reversal of rejection after treatment. Otherwise additional agents will need to be added. A biopsy is obtained 1 week after initial biopsy showed rejection and then 1 week after therapy complete. If ATGAM or OTK3 is used biopsy should be obtained at the end of a course of therapy (usually 7 to 14 days) and then again 1 week later off therapy.

41. Complications - Rejection • Allograft vasculopathy (Chronic rejection): Transplant coronary artery disease that is the leading cause of death in patients more than 1 year after transplantation. • Likely a result of a proliferative response to immunologically mediated endothelial injury (chronic humoral rejection). • It differs from native CAD in that it is manifested by concentric stenoses, predominately subendocardial location, lack of calcification, can be rapidly progressive and lack of angina pectoris. • Risk factors include degree of histocompatibility, hypertension, hyperlipidemia, obesity, and CMV infection.

42. Complications – Rejection Allograft Vasculopathy • Treatment is mainly prevention with statins, diltiazem, and antioxidant vitamins. Rapamycin is an agent that has shown promise in preventing this complication. • Treatment with percutaneous interventions and CABG is limited due to its diffuse nature and subendocardial locations. • Retransplantation for this disorder is an option, but retrospective analysis have shown this approach does not improve mortality as patients do significantly worse with a second transplant as compared with the first.

43. Complications - Infection • There are two peak infection periods after transplantation: • The first 30 days postoperatively: nosocomial infections related to indwelling catheters and wound infections. • Two to six months postoperatively: opportunistic immunosuppresive-related infections. • There is considerable overlap, however as fungal infections and toxoplasmosis can be seen during the first month. • It is important to remember that immunosuppressed transplant patients can develop severe infections in unusual locations and remain afebrile.

44. Opportunistic Infections • CMV: most common infection transmitted donor to recipient. • Manifested by fever, malaise, and anorexia. Severe infection can affect the lungs, gastrointestinal tract, and retina. • If donor is CMV positive and the recipient is CMV negative, prophylaxis with IV ganciclovir or foscarnet is given for 6 weeks and followed by longterm oral prophylaxis with acyclovir. • If the recipient is CMV positive a less potent regimen can be used. • Bone marrow toxicity related to treatment can occur and be confused with that due to azathioprine treatment.

45. Opportunistic Infections • Toxoplasma gondii: Primary infection can be serious while reactivation is rarely a serious clinical problem. • Manifested as encephalitis, myocarditis, or pneumonitis. • Treated with pyrimethamine and sulfadiazine. • Pneumocystis carinii: Prophylactic therapy with TMP/Sulfa is highly effective in preventing progressive bilateral interstitial pneumonia caused by this protozoan. • Dapsone (Requires G6PD testing) and pentamidine aerosols (does not protect lung apices) are quite effective for those with sulfa allergies.

46. Opportunistic Infections • Aspergillus organisms: Invasive Aspergillus infection, typically of the lung or upper respiratory tract is extremely difficult to manage. • It is fortunately rare, and usually occurs among patients who are severely immunocompromised from use of antilymphocyte antibodies. • Standard treatment is with IV Amphotericin.

47. Complications - Malignancy • Transplant recipients have a 100-fold increase in the prevalence of malignant tumors as compared with age-matched controls. • Most common tumor is posttransplantation lymphoproliferative disorder (PTLD), a type of non-Hodgkin’s lymphoma believed to be related to EBV. • The incidence is as high as 50% in EBV-negative recipients of EBV-positive hearts. • Treatment involves reduction of immunosuppressive agents, administration of acyclovir, and chemotherapy for widespread disease. • Skin cancer is common with azathioprine use. • Any malignant tumor present before transplantation carries the risk for growth once immunosuppresion is initiated because of the negative effects on the function of T-cells.

48. Complications - Hypertension • As many as 75% of transplant recipients treated with cyclosporine or corticosteroids evential develop hypertension. • Treatment is empiric with a diuretic added to a calcium channel blocker, B-blocker, or Ace inhibitor. • If either diltiazem or verapamil is used, the dosage of cyclosporin should be reduced.

49. Complications - Dyslipidemia • As many as 80% of transplant recipients eventually have lipid abnormalities related to immunosuppression medications. • These dyslipidemias have been linked to accelerated allograft arteriopathy. • These disorders should be treated aggressively with statins and fibrates to hopefully alleviate transplant coronary vasculopathy.

50. Complications – Tricuspid Regurgitation • A rare complication is tricuspid regurgitation caused by biotome-induced trauma to the valve apparatus that rarely requires valve replacement.