Cardiac Transplantation

Published on 17/05/2015 by admin

Filed under Internal Medicine

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 1923 times

Chapter 29

Cardiac Transplantation

1. How many heart transplantations are performed in the U.S. each year? What are the most frequent causes of heart disease requiring cardiac transplantation?

    Dr. Christiaan Barnard performed the first human allograft transplantation in 1967. Approximately 2000 to 2200 hearts are currently transplanted each year, most commonly for nonischemic cardiomyopathy (46%) and coronary artery disease (40%), as well as for congenital heart disease, valvular heart disease, and other indications, including retransplantation.

2. List common indications for heart transplantation.

image Severe heart failure (New York Heart Association [NYHA] class III or IV) with poor short-term prognosis despite maximal medical therapy, requiring continuous inotropic therapy, requiring mechanical support (e.g., balloon pump, left ventricular assist device [LVAD], extracorporeal membrane oxygenation [ECMO])

image Restrictive or hypertrophic cardiomyopathy with NYHA class III or IV symptoms

image Refractory angina despite medical therapy, not amenable to revascularization, with poor short-term prognosis

image Recurrent or refractory ventricular arrhythmias, despite medical and/or device therapy

image Complex congenital heart disease with progressive ventricular failure not amenable to surgical or percutaneous repair

image Unresectable low-grade tumors confined to the myocardium, without evidence of metastasis

3. What baseline evaluations are obtained in the pretransplantation workup?

    Pretransplantation evaluation serves the purpose of assessing a patient’s severity of heart failure, mortality benefit from surgery, comorbidities, and potential contraindications to surgery. Factors important in transplantation evaluation are given in Box 29-1.

Box 29-1   FACTORS IMPORTANT IN THE EVALUATION OF PATIENTS FOR CARDIAC TRANSPLANTATION

Psychosocial Evaluation

4. What are contraindications to heart transplantation?

    Contraindications include any noncardiac conditions that may decrease a patient’s survival, and increase risk of rejection or infection, and are listed in Box 29-2.

Box 29-2   ABSOLUTE AND RELATIVE CONTRAINDICATIONS TO HEART TRANSPLANTATION

AIDS, acquired immunodeficiency syndrome; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HIV, human immunodeficiency virus.

5. Define allotransplantation versus xenotransplantation, and orthotopic versus heterotopic transplantation.

    Allotransplantation involves transplantation of cells, tissue, or organs between same species Xenotransplantation involves transplantation of cells, tissue, or organs between different species. During orthotopic heart transplantation, the donor heart is transplanted in place of the recipient’s heart. There are two anastomotic approaches used (Fig. 29-1).

During heterotopic heart transplantation, the recipient’s heart is left in the mediastinum, and the donor heart is attached “parallel” to the recipient heart (see Fig. 29-1).

6. Define ischemic time of the donor heart. Why is it important?

    The cold ischemic time is the time interval between removal of the donor heart and the implantation in the recipient. During this interval, ischemic injury can occur to the heart due to lack of perfusion. Myocardial preservation is achieved with hypothermia and placement of the heart in a solution mimicking intracellular milieu to prevent cellular edema and/or acidosis, and maintain ATP supply for membrane function. A prolonged ischemic time can lead to irreversible damage to the harvested organ. A cold ischemic time of more than 5 hours is associated with a higher incidence of cardiac allograft dysfunction and decreased transplant recipient survival.

7. What is the estimated graft survival at 1 year, 3 years, 5 years, and 10 years posttransplantation? What are the common causes of death?

    Based on the 2007 U.S. Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR) report, graft survival approximates 88% at 1 year, 73% at 5 years, and 50% at 10 years posttransplantation.

    The major causes of death posttransplantation are as follows:

8. What is cardiac allograft vasculopathy (CAV)? Describe its pathophysiology, incidence, risk factors, and outcome.

    Also known as transplant vasculopathy or transplant coronary artery disease (CAD), CAV is the progressive narrowing of the coronary arteries of the transplanted heart. Angiographic incidence of CAV is approximately 30% at 5 years and 50% at 10 years. CAV is associated with a significantly increased risk of death. After the first year posttransplantation, CAV is the second most common cause of death (after malignancy). In CAV, there is diffuse, concentric proliferation of the intimal smooth muscle cells and it typically involves the entire length of the coronary artery. In contrast, conventional atherosclerosis results from fibrofatty plaque resulting in concentric or eccentric focal lesions. The etiology of CAV remains unclear, but both immunologic (cellular and/or humoral rejection, human leukocyte antigen [HLA] mismatch) and nonimmunologic (cytomegalovirus [CMV] infection, hypercholesterolemia, older age and/or male donors, younger recipients, history of CAD, diabetes mellitus [DM], and insulin resistance) factors have been implicated

    Note that cardiac transplant recipients can also develop conventional atherosclerosis through two main mechanisms:

9. List infections that are encountered early and late after cardiac transplantation.

    Early (<1 month):

Intermediate (1-6 months):

Late (>6 months):

10. What type of malignancies are encountered posttransplantation? List incidence, time course, and prognosis.

    Malignancy risk in cardiac transplant recipients approaches 1% to 4% per year and is 10 to 100 times higher than that in age-matched controls. Malignancy is the major cause of late death in heart transplant recipients and is thought to be a result of chronic immunosuppression. The most common malignancy encountered is skin cancer (29% at 15 years). Squamous cell carcinoma is more prevalent in transplantation patients compared to basal cell cancer, which is more prevalent in the general population. Non-skin malignancies are seen in 18% of cardiac transplant recipients at 15 years (prostate, lung, bladder, renal, breast, and colon cancer).

    Posttransplantation lymphoproliferative disorder (PTLD) is diagnosed in 6% of cardiac transplant recipients at 15 years. PTLD can be associated with primary or reactivated EBV infection, which leads to abnormal proliferation of lymphoid cells and can involve gastrointestinal, pulmonary, and central nervous systems; PTLD usually presents as non-Hodgkin’s lymphoma (predominately B cell type). Risk of PTLD varies with allograft type, immunosuppression, EBV immunity prior to transplantation, and previous CMV infection.

11. Describe potential arrhythmias encountered posttransplantation.

    The donor heart is disconnected from sympathetic and parasympathetic innervation. Therefore, the resting heart rate is higher than normal (90-110 bpm) and atropine has no effect on the denervated heart. Early posttransplantation arrhythmias can be a result of surgical trauma to the sinoatrial (SA) or atrioventricular (AV) nodes, prolonged ischemic time, surgical suture lines, and rejection. Late-occurring arrhythmias may suggest rejection or the presence of transplant vasculopathy. Potential arrhythmias encountered posttransplantation include the following:

image Sinus node dysfunction occurs in up to 50% of cardiac transplant recipients. Sinus node dysfunction early after transplantation does not appear to affect mortality, but has been associated with increased morbidity. Treatment of sinus bradycardia includes temporary pacing, intravenous (isoproterenol or dobutamine) or oral (theophylline or terbutaline) therapy in the immediate postoperative period. However, severe persistent bradycardia may require permanent pacemaker placement (up to 15% of patients).

image AV nodal block is rarely encountered; its occurrence may indicate the presence of transplant vasculopathy and has been associated with increased mortality.

image Atrial arrhythmias: Transient atrial arrhythmias, especially premature atrial contractions (PACs) are common in the early postoperative period; their clinical significance remains unclear, but frequent occurrences should prompt evaluation for rejection. Atrial fibrillation or flutter can occur in up to 25% of cardiac transplant recipients; late occurrence warrants evaluation for rejection. Treatment includes rate control with beta-adrenergic blocking agents (β-blockers), calcium channel blockers, cardioversion, overdrive pacing, and treatment for rejection. Atrial flutter can be treated with radiofrequency ablation.

image Ventricular arrhythmias: Premature ventricular contractions (PVCs) are not uncommon early after cardiac transplantation, and their clinical significance is unknown. However, nonsustained ventricular tachycardia (>3 consecutive PVCs) has been associated with rejection and transplant vasculopathy. Sustained ventricular tachycardia or ventricular fibrillation are associated with poor prognosis and indicate severe transplant vasculopathy or high-grade rejection. Treatment includes correcting electrolyte abnormalities, intravenous amiodarone or lidocaine, defibrillation, and prompt evaluation for rejection and transplant vasculopathy.

12. What are the clinical signs and symptoms associated with acute cardiac transplant rejection (allograft rejection)?

    Around 40% to 70% of cardiac transplant recipients experience rejection within the first year posttransplantation. Most episodes occur in the first 6 months, with a decrease in frequency after 12 months. Acute allograft rejection is the leading cause of death in the first year after transplantation; this emphasizes the importance of early diagnosis and treatment. The majority of patients are asymptomatic early in the course of rejection; therefore, routine biopsies are necessary to assist in the diagnosis of rejection.

    The clinical presentation of rejection can be variable. Patients may present with nonspecific constitutional symptoms such as fever, malaise, fatigue, myalgias, joint pain, and flu-like symptoms. Signs and symptoms of LV and RV dysfunction including severe fatigue, loss of energy, listlessness, weight gain, sudden onset of dyspnea, syncope/presyncope, orthopnea/paroxysmal nocturnal dyspnea, and/or abdominal bloating/nausea/vomiting. Physical exam can reveal elevated jugular venous pulse, peripheral edema, hepatomegaly, S3 or S4 gallop, and lower than usual blood pressure. Signs of cardiac irritation may include sinus tachycardia, bradycardia, arrhythmias, pericardial friction rub, or new pericardial effusion by echo.

13. List the different types of acute allograft rejection.

    Allograft rejection occurs as a result of recipient immune response to donor heart antigens.

14. Describe the grading and immunohistologic findings of acute cellular rejection (ACR) and acute antibody-mediated rejection (AMR).

    The Standardized Biopsy Grading system for ACR and AMR was established in 1990 (later revised in 2004) by the International Society for Heart and Lung Transplantation (ISHLT):

image The rejection grades and corresponding histologic findings for ACR are presented in Table 29-1.

TABLE 29-1

ACUTE CELLULAR REJECTION (ACR)

Rejection Grade Histologic Findings
Grade 0R No rejection
Grade 1R, mild Interstitial and/or perivascular infiltrate with ≤1 focus of myocyte damage
Grade 2R, moderate ≥2 Foci of infiltrate with associated myocyte damage
Grade 3R, severe Diffuse infiltrate with multifocal myocyte damage, ± edema, hemorrhage, or vasculitis

image The rejection grades and corresponding histologic findings for AMR are presented in Table 29-2.

TABLE 29-2

ACUTE ANTIBODY-MEDIATED REJECTION (AMR)

Rejection Grade Histologic Findings
AMR 0 Negative for acute AMR
No histologic or immunopathologic features of AMR
AMR 1 Positive for AMR
Histologic∗ features of AMR
Positive immunofluorescence/immunoperoxidase† staining (+CD68, C4d)

∗Histologic features of AMR: myocardial capillary injury with endothelial swelling and accumulation of perivascular macrophage.

†Immunohistochemistry shows deposition of immunoglobulin (IgG, M, A), complement (C3d, C4d, C1q), and CD68 staining for macrophage in capillaries (using CD31 or CD34 vascular markers).

15. How is allograft rejection diagnosed?

16. How is an EMB performed and what are potential complications?

    During the first year posttransplantation, scheduled surveillance biopsies are performed. After the first year, the need for a biopsy is dictated by clinical suspicion for rejection. A sheath is placed into the right internal jugular vein or femoral vein, and a flexible bioptome is introduced via the sheath and advanced into the right ventricle by fluoroscopic guidance. Three to four samples are obtained, preferably from the interventricular septum.

    Potential complications of biopsies include:

17. What is induction therapy? Describe its role in cardiac transplantation.

    Induction therapy involves use of cytolytic antilymphocyte antibodies to suppress donor immune response, which is most vigorous shortly after transplantation. Induction agents have not consistently been shown to decrease rates of rejection and have been associated with increased risk of infection and malignancy. However, induction therapy is beneficial in certain situations.

18. What is the incidence of ACR? Describe predisposing factors and treatment.

    Approximately 40% of cardiac transplant recipients have ACR (grade >1R) in the first year after transplantation. Rejection frequency declines after the first year posttransplantation. Risk factors for ACR include early posttransplantation period; female donor; young, African American, or female recipients; and HLA mismatches. Treatment generally consists of high-dose corticosteroids, antithymocyte globulin (ATG), or muromonab-CD3 (OKT3) (Table 29-4).

TABLE 29-4

ACUTE CELLULAR REJECTION THERAPIES

Rejection Grade Therapy
1R No treatment
1R + sx/hemodynamic compromise IV steroids followed by oral taper, repeat biopsy in 1 week
2R High dose oral or IV steroids
2R + sx/hemodynamic compromise IV steroids followed by taper, repeat biopsy in 1 week
ATG or muromonab-CD3 if persistent rejection despite 2 courses of steroid therapy
3R ATG or muromonab-CD3, repeat biopsy after course and again in 1 week
Recalcitrant rejection Photopheresis, total lymphoid radiation

ATG, Antithymocyte globulin; sx, symptoms.

19. Describe predisposing risk factors and treatment for AMR?

    AMR has a worse prognosis than ACR, with higher rates of mortality, graft loss, and incidence of transplant vasculopathy. Predisposing factors for AMR include prior cardiac transplantation, transfusion, pregnancy (exposure to husband’s HLA through the fetus), ventricular assist device placement (which can result in prominent B cell activation and production of anti-HLA antibodies), CMV infection, and prior muromonab-CD3 therapy. AMR treatment has not been standardized. Therapies currently include high dose corticosteroids, plasmapheresis, intravenous immunoglobulins, rituximab, antilymphocyte antibodies (ATG or muromonab-CD3), intravenous heparin, target of rapamycin (TOR) inhibitors, cyclophosphamide, and photopheresis. Active CMV infection has been associated with AMR. Thus, patients with AMR should be evaluated for de novo or reactivation of CMV infection, and treated if infection is present.

20. Describe typical maintenance immunosuppression therapy.

    The goal of maintenance immunosuppression is to suppress the recipient immune system from rejecting the transplanted heart. This “triple therapy” regimen consists of:

Approximately 60% of cardiac transplant recipients will not require long-term steroid use. Steroid withdrawal may be attempted after 1 year posttransplantation in patients without episodes of rejection. Newer agents include the TOR inhibitors (sirolimus, everolimus). Currently, the TOR inhibitors are not used as part of the standard maintenance therapy but are added in patients with accelerated transplant vasculopathy, worsening renal function on calcineurin inhibitors, and frequent rejections on standard triple maintenance therapy. Note that mycophenolate mofetil (MMF) or azathioprine are stopped when sirolimus or everolimus are added, to avoid excessive immunosuppression (Table 29-5).

21. What are common medical conditions encountered in posttransplantation patients?

22. Describe adverse effects encountered with calcineurin inhibitor use and potential drug interactions that may lead to calcineurin toxicity.

image Hypertension: greater than 70% by 1 year and 95% by 5 years after transplantation

image Renal dysfunction: greater than 25% by 1 year and 5% progress to end-stage renal disease within 7 years after transplantation

image Rhabdomyolysis when used concurrently with HMG-CoA reductase inhibitors (statins), because calcineurin inhibitors inhibit metabolism of certain statins (lovastatin, simvastatin, cerivastatin, and atorvastatin). Fluvastatin, pravastatin, and rosuvastatin are less likely to be involved in this type of interaction.

image Calcineurin toxicity is characterized by neurologic symptoms (headaches, tremor, confusion, agitation, delirium, expressive aphasia, and seizures), nephrotoxicity, and hypertension. The enzyme CYP3A4 metabolizes calcineurin inhibitors, and inhibitors of CYP3A4 can lead to increased drug levels and adverse effects. CYP3A4 inhibitors include:

23. How do patients with transplant vasculopathy clinically present? What invasive and noninvasive tests are used to assist in the diagnosis of transplant vasculopathy?

    Because transplanted hearts are denervated, cardiac transplant recipients typically do not present with angina when they develop transplant vasculopathy. Clinical manifestations include silent myocardial infarctions, symptoms of heart failure, syncope, sudden cardiac death, and arrhythmias.

24. Describe strategies to prevent and treat cardiac allograft vasculopathy.

    Although no effective preventive strategy for CAV has been identified, several factors have been associated with a lower incidence of CAV.

Treatment of cardiac allograft vasculopathy may include the following:

25. When should mechanical circulatory support device (MCSD) implantation be considered?

    A limited number of donor hearts and an increasing number of patients with NYHA class IV symptoms have created a demand for alternative treatments for end-stage heart failure. One strategy is the implantation of an MCSD or left ventricular assist device (LVAD).

    Indications for LVAD implantation include:

26. What is gene expression profiling (GEP) and how is it used in the diagnosis of rejection?

    GEP evaluates the transcription of genes involved in acute rejection and myocardial injury. GEP is performed on peripheral blood analysis. The AlloMap score (XDx, Inc., Brisbane, Calif.) uses GEP to grade the risk of presence of rejection. The AlloMap score has been shown to have a high negative predictive value for lower scores, but the positive predictive value for high scores is low. Thus, the use of AlloMap is recommended only in select patients: to rule out the presence of ACR of grade 2R or greater in low-risk patients, between 6 months and 5 years after cardiac transplantation.

Bibliography, Suggested Readings, and Websites

1. Department of Transplantation Immunology, University of Heidelberg: Collaborative Transplant Study website. Available at: www.ctstransplant.org. Accessed May 1, 2012.

2. Eisen, H.J. Immunosuppression on the horizon. Heart Fail Clin. 2007;3:43–49.

3. The International Society for Heart and Lung Transplantation: ISHLT website. Available at: www.ishlt.org. Accessed May 1, 2012.

4. Jessup, M., Banner, N., Brozena, S., et al. 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;25:1003–1023.

5. The Journal of Heat and Lung Transplantation: JHLT website. Available at: www.jhltonline.org. Accessed May 1, 2012.

6. Kirklin, J.K., Young, J.B., McGiffin, D.C. Heart transplantation. Philadelphia: Churchill Livingstone; 2002.

7. Kobashigawa, J.A. Contemporary concepts in noncellular rejection. Heart Fail Clin. 2007;3:11–15.

8. OPTN/SRTR: 2009 U.S. Organ Procurement and Transplantation Network (OPTN) and the Scientific Registry of Transplant Recipients (SRTR) Annual Report: Transplant Data 1999-2008. Available at: http://optn.transplant.hrsa.gov/ar2009/default.htm. Accessed May 1, 2012.

9. Sipahi, I., Starling, R.C. Cardiac allograft vasculopathy: an update. Heart Fail Clin. 2007;3:87–95.

10. Steinman, T.I., Becker, B.N., Frost, A.E., et al. Guidelines for the referral and management of patients eligible for solid organ transplantation. Transplantation. 2001;71:1189–1204.

11. Stewart, S., Winters, G.L., Fishbein, M.C., et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005;24:1710–1720.

12. Stehlik, J., Edwards, L.B., Kucheryavaya, A.Y., et al. The Registry of the International Society of Heart and Lung Transplantation: Twenty-eighth official adult heart transplant report—2011. J Heart Lung Transplant. 2011;30:1078–1094.

13. United Network for Organ Sharing: UNOS website. Available at: www.unos.org. Accessed May 1, 2012.

Related posts:

Bedside Hemodynamic Monitoring Cardiac Catheterization, Angiography, IVUS, and FFR Percutaneous Coronary Intervention Echocardiography Preoperative Cardiac Evaluation Cardiovascular Physical Examination