Online Medical Reference

Heart Transplantation

Mohamad H. Yamani and David O. Taylor

Published: August 2010

Cardiac transplantation has emerged as a viable therapeutic strategy for select patients with end-stage heart disease, offering extended survival and improved quality of life. Patients with severe heart failure have a 1- to 2-year mortality rate approaching 50%, despite advanced medical treatment. Approximately 4000 heart transplantation procedures are performed annually worldwide. In the United States, approximately 3000 patients are awaiting transplantation, but only 2000 patients undergo transplantation annually because of lack of donor hearts. Long-term outcomes after transplantation have improved with the advances made in transplant candidate selection, surgical techniques, immunosuppressive modalities, and postoperative care. The current survival rate after heart transplantation has been reported as approximately 50% at 12 years by the International Society for Heart and Lung Transplantation (ISHLT) registry.

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Initial Considerations

Recipient and Donor Selection

The paucity of the donor pool demands a very careful patient- selection process to ensure appropriate candidacy. A thorough search for reversible or surgically amenable cardiac disease must be completed and optimal medical management implemented before transplantation is considered. Early referral to a heart-failure cardiologist is recommended to evaluate for appropriate candidacy. Certain basic tests are required in the evaluation process and include a right heart catheterization to evaluate hemodynamics and, in particular, to evaluate for any reversible pulmonary hypertension component. A metabolic stress test is also indicated to evaluate peak oxygen consumption. Certain inclusion criteria (Box 1) and exclusion criteria (Box 2) must be met for a successful post-transplantation outcome. Routine blood tests, including screening serology for cytomegalovirus, toxoplasmosis, Epstein virus, hepatitis B, and hepatitis C, are also indicated. Once inclusion and exclusion criteria are met, the patient is listed according to urgency code status (see later).

Box 1 Indications for Cardiac Transplantation
Refractory heart failure requiring continuous inotropic support
Cardiogenic shock requiring mechanical assistance (e.g., ventilator, intra-aortic balloon pump, ventricular assist device, total artificial heart) with, at worst, reversible end-organ damage
Congestive heart failure, New York Heart Association (NYHA) Class III or IV symptoms, with objective evidence of impaired functional capacity (peak oxygen consumption <14 mL/kg/min), despite optimal medical therapy
Refractory angina, despite maximal medical therapy, and not amenable to revascularization
Refractory life-threatening ventricular arrhythmias, despite maximal antiarrhythmic therapy by all appropriate conventional medical and surgical modalities (multiple firings from an ICD for documented VT and VF)
Congenital heart disease with progressive ventricular failure that is not amenable to conventional surgical repair
Severe hypertrophic or restrictive cardiomyopathy, with NYHA Class IV symptoms
Cardiac tumors confined to the myocardium, with a low likelihood of metastasis at time of transplantation

ICD, implantable cardioverter-defibrillator; VF, ventricular fibrillation; VT, ventricular tachycardia.

Box 2 Absolute and Relative Contraindications to Cardiac Transplantation
Pulmonary artery systemic pressure >60 mm Hg, mean transpulmonary gradient >15 mm Hg, and/or peripheral vascular resistance >5 Wood units on maximal vasodilator therapy
Active infection (unless associated with left ventricular assist device)
Active peptic ulcer disease
Active diverticulitis
Irreversible severe hepatic disease
Irreversible severe renal disease
Morbid obesity (body mass index >35 kg/m2)
Severe diabetes mellitus, with end-organ damage
Severe peripheral vascular disease
Recent stroke (unless associated with left ventricular assist device)
Acute pulmonary embolism (<6 wk)
Active neoplasm (must be malignancy-free for at least 5 yr)
Current alcohol or drug abuse
Ongoing tobacco use
Irreversible severe pulmonary disease, with FEV1 <1 L or FVC <50%
Severe psychiatric or cognitive impairment
Repeated noncompliance with medications or follow-up
Lack of family or social support

FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity.

Donor selection is influenced by many factors, including ABO blood type compatibility, size similarity between the donor and recipient, presence of intrinsic cardiac disease, and presence of transmissible infectious or malignant diseases. The risk of using a specific donor heart is always balanced against the risk of short-term death in a particular recipient. To screen for donor cardiac disease, electrocardiography, echocardiography, and sometimes coronary angiography are used. Some donor hearts with significant coronary artery or valvular disease have been transplanted successfully with simultaneous bypass surgery or valve replacement, but doing so is not yet standard care. Brain death can cause time-dependent changes in left ventricular function that may be related to catecholamine release. Donor heart dysfunction may be reversible, and thyroid hormone is frequently administered to improve donor heart function. Clearly, using an irreversibly damaged donor heart is to be avoided.

Transplantation Urgency Code Status

Once patients are approved for transplantation, they are listed according to the medical urgency status and severity of the illness (Table 1). The median waiting time for transplantation is approximately 9.4 months in the United States. The waiting time to transplantation depends on several factors, including listed status, body weight, blood group, and other differences between recipient and donor. It is estimated that 15% to 20% of patients die while waiting for a transplant.

Table 1 Transplantation Urgency Code Status
Code Status Description
1A Patients who are on inotropic support and receiving mechanical support, or on a ventilator or in the intensive care unit, with a pulmonary artery catheter in place for hemodynamic monitoring
1B Patients who are on inotropic support but not meeting 1A criteria or who have had a ventricular assist device longer than 30 days
2 Patients who are waiting at home on medical therapy
7 Patients who are on hold because of an intervening medical illness, making them inappropriate candidates for transplantation

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Heart Transplantation Surgery

Three implantation techniques are available: biatrial technique, bicaval technique, and the rarely used heterotopic technique. The key to successful transplantation is the donor ischemic time, defined as the time from aortic cross-clamping in the donor to release of the aortic cross-clamping in the recipient. An acceptable ischemic time is considered to be less than 4 hours. Concern about the loss of normal atrial anatomy using the biatrial technique has led to the more frequent use of the bicaval technique. The bicaval technique can result in a longer donor heart ischemic time but is associated with lower right atrial pressure, lower incidence of atrial tachyarrhythmias, and less tricuspid valve incompetence. Heterotopic cardiac transplantation can be performed with the donor heart placed in the right lower thorax in parallel to the recipient heart, which is left in place. The indications for heterotopic cardiac transplantation include significant pulmonary hypertension, a small donor heart, and a donor heart with anticipated poor initial function. This technique accounts for only 0.3% of all heart transplantation procedures.

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Post-transplantation Cardiac Function

The function of the newly transplanted cardiac allograft is influenced by an interplay of several important physiologic factors that include allograft denervation, ventricular loading conditions, hormonal milieu, myocardial injury, donor-recipient size relation, pulmonary performance, and atrial function.

Serial ventricular function evaluation by Doppler echocardiography has suggested the presence of diastolic dysfunction, which is a common phenomenon early after heart transplantation. Prior hemodynamic studies have also noted a restrictive pattern that usually resolves within days or weeks but may persist or recur later because of cell-mediated rejection or hypertrophy.

During the first week after cardiac transplantation, there is generally an increase in the severity of mitral, tricuspid, and aortic regurgitation. These valvular regurgitations are usually asymptomatic at rest, except for tricuspid regurgitation, which is associated with right-sided heart failure in more than 50% of patients in the early postoperative period.

Recently, tissue Doppler imaging has emerged as a technique that permits evaluation of myocardial relaxation velocities and allows estimation of ventricular filling pressures following heart transplantation. Because allograft rejection results in increased myocardial stiffness and abnormal myocardial relaxation tissue, Doppler imaging has been a useful noninvasive tool for the diagnosis of rejection and may have a role as a screening technique if ongoing research confirms its sensitivity and specificity.

Cardiac Allograft Rejection

After heart transplantation, proinflammatory cytokines are elaborated and recipient inflammatory cells are recruited into the cardiac allograft. The sequence of events leading to cardiac allograft rejection encompasses antigen recognition, primary and secondary (costimulatory) signals for T cell activation, and T cell proliferation and differentiation. Patients may be asymptomatic or may experience a spectrum of symptoms, ranging from mild exertional dyspnea to overt heart failure symptoms and arrhythmias resulting in syncope, cardiac arrest, or both, depending on the severity of rejection. Echocardiography is helpful to evaluate graft function, but left ventricular function may be preserved in the early stages. Endomyocardial biopsy is the gold standard procedure to establish the diagnosis of rejection (see later).

There are three types of rejection: hyperacute, acute cellular, and acute vascular (antibody-mediated) rejection. Hyperacute rejection is a result of preformed donor-specific antibodies in the recipient. It is a vigorous immune response that takes place within minutes to hours. The outcome, without repeat transplantation or total artificial heart support, is uniformly fatal. The best method for avoiding hyperacute rejection is to avoid transplanting a donor heart into a patient who is sensitized to the donor (a positive donor-specific crossmatch). Acute cellular rejection is the most common form of rejection and occurs at least once in approximately 50% of heart transplant recipients (Fig. 1). Even though the propensity toward allograft rejection decreases over time and almost 50% of the rejection episodes occur in the first 2 to 3 months, late rejection can and does occur. Vascular rejection may manifest by otherwise unexplained cardiac allograft dysfunction, with or without histologic evidence. Histologic evidence is a scant cellular infiltrate but abundant colocalized immunoglobulin and complement components in the allograft microvasculature seen on one or more biopsy specimens (Fig. 2). In addition, vascular rejection may manifest only histologically in the absence of allograft dysfunction. Vascular rejection is more difficult to treat than acute cellular rejection and is more often accompanied by hemodynamic compromise or instability. As a result, vascular rejection is associated with a worse prognosis and appears to increase the risk of cardiac allograft vasculopathy (CAV) almost tenfold.

Surveillance Endomyocardial Biopsy

Endomyocardial biopsy remains the gold standard for the diagnosis of acute rejection after cardiac transplantation. Recently, molecular gene expression testing in peripheral blood (AlloMap) has been used as a noninvasive tool to detect quiescence and acute rejection. This test has a high negative predictive value, approaching 95%; however, it has low sensitivity. The most commonly used grading scheme for the diagnosis and staging of rejection is that of the ISHLT (Table 2). Rejection is the leading cause of death in the first year after heart transplantation, and accounts for approximately 20% of all deaths. The frequency of surveillance biopsy varies among centers. In general, routine endomyocardial biopsies are performed weekly for the first month, then every 2 weeks during the second month, and increased to monthly through months 8 to 12. After 1 year, biopsies are done every 4 to 6 months. Following a treated episode of rejection, the endomyocardial biopsy is generally repeated within 14 days to ensure adequate treatment.

Table 2 Revised ISHLT Standardized Endomyocardial Biopsy Grading Scheme
Revised Grading Old Grading Criteria
0 0 Normal myocardium
1 1A Focal lymphocytic infiltrate, without myocyte necrosis
1B Diffuse but sparse lymphocytic infiltrate, without myocyte necrosis
2 One focus of aggressive lymphocytic infiltrate, focal myocyte injury, or both
2 3A Multifocal aggressive lymphocytic infiltrate, focal myocyte injury, or both
3 3B Diffuse lymphocytic infiltrate with myocyte necrosis
4 4 Diffuse, aggressive, polymorphous infiltrate with necrosis (with or without edema, hemorrhage, vasculitis)

ISHLT, International Society for Heart and Lung Transplantation.

Although endomyocardial biopsy is usually considered safe, it entails some procedural risk but has few significant long-term sequelae. Complications during biopsy include hematoma, pneumothorax, hemothorax, cardiac perforation, arrhythmias, and conduction abnormalities, but these complications are rare. Occasional cases of hepatitis B transmission have been reported, and coronary artery fistula formation has been described in 2.9% of patients, most of which close spontaneously without long-term clinical sequelae. Venous thrombosis has also been reported but is unusual. Iatrogenic tricuspid regurgitation is a known but fortunately infrequent complication.

Immunosuppression

Immunosuppression is used to prevent rejection and is generally required for life. Early rejection prophylaxis involves the use of multiple agents (Table 3). Generally, triple therapy is used, consisting of cyclosporine or tacrolimus; azathioprine, mycophenolate mofetil, or sirolimus; and corticosteroids. Triple therapy has proved to be effective for most patients. Drug level monitoring is important to ensure adequacy of immunosuppression and avoid unwanted adverse effects, mainly nephrotoxicity. Therapeutic levels are variable in relation to time since transplantation (Table 4). Because the propensity for rejection decreases over time, dosages of all three drugs may be decreased accordingly. Cyclosporine and tacrolimus are usually maintained long term at levels less than 50% of those used early after transplantation. Long-term dosages of mycophenolate mofetil generally decrease from 3000 to 2000 mg/day. Prednisone can be withdrawn in some patients who demonstrate a low propensity to reject or if they experience steroid-related adverse effects.

Table 3 Pharmacology of Commonly Used Immunosuppressive Agents
Agent Mechanism of Action Administration Toxicity Drug-Drug Interactions
Cyclosporine Binds to cyclophilin, inhibits calcineurin-dependent transcription and translation of cytokine genes, particularly interleukin (IL)-2 PO or IV, oral to IV dose adjustment is 3 : 1; oral dosage 3-6 mg/kg/day, targeted to level Renal effects, hypertension, gingival hyperplasia, hirsutism, tremor, headache, paresthesias, flushing Metabolism decreased by ketoconazole, diltiazem, verapamil, erythromycin, cimetidine, grapefruit; metabolism increased by phenytoin, phenobarbital, isoniazid, rifampin, carbamazepine
Tacrolimus Binds to FK-binding protein, inhibits calcineurin-dependent transcription and translation of cytokine genes, particularly IL-2 PO or IV, oral to IV dose adjustment is 5 : 1; oral dosage 0.05-0.15 mg/kg/day, targeted to level Renal effects, hypertension, tremor, headache, flushing, paresthesias, glucose intolerance Similar to cyclosporine
Azathioprine Inhibits purine ring biosynthesis, decreasing synthesis of DNA and RNA PO or IV, no significant oral to IV adjustment; 1-2 mg/kg/day; white blood cell (WBC) count to remain >4000/mm3 Macrocytic anemia, leukopenia, pancreatitis, cholestatic jaundice, hepatitis Allopurinol slows metabolism by inhibiting xanthine oxidase
Mycophenolate mofetil Inhibits inosine monophosphate dehydrogenase, inhibiting the de novo pathway for guanine nucleotide biosynthesis PO or IV, no significant oral to IV adjustment; 2000-6000 mg/day Gastrointestinal distress, leukopenia No significant interactions
Sirolimus Binds to FK-binding protein, inhibits IL-2– and IL-6–driven events PO, loading dose 6 mg, then 2 mg/day Hypertriglyceridemia, thrombocytopenia, leukopenia Metabolism decreased by diltiazem and ketoconazole; metabolism increased by rifampin
Corticosteroids Lymphocytolysis, inhibits release and action of various interleukins, interferes with antigen receptor interactions PO or IV with methylprednisolone; maintenance dosage of prednisone is 0.0-0.1 mg/kg/day Cushingoid habitus, glucose intolerance, hyperlipidemia, hypertension, cataracts, myopathy, osteoporosis Multiple drug interactions, none clinically significant

Table 4 Immunosuppression Drug Level Monitoring
Immunosuppressive Agent Therapeutic Level
Cyclosporine (ng/mL)
    0-3 mo 300-350
    3-12 mo 225-250
    After 1 yr 150-175
Tacrolimus (ng/mL)
    0-3 mo 15-20
    3-12 mo 10-15
    After 1 yr 5-10
Mycophenolate mofetil (mg/L) 2-4

The treatment of cardiac allograft rejection depends on several factors, including severity of rejection (ISHLT grade of endomyocardial biopsy specimens), time since transplantation, immunosuppressive history, and hemodynamic status of the patient. In treating rejection, one generally optimizes or increases the dosages of maintenance immunosuppressors. Mild rejection in hemodynamically stable patients—those without evidence of allograft dysfunction—is not treated. Moderate rejection in the absence of hemodynamic instability is usually treated initially with a several-day course of intravenous or high-dose oral corticosteroids. In corticosteroid refractory rejection or in rejection episodes associated with hemodynamic instability, an antilymphocyte antibody such as OKT3 or an antithymocyte globulin is added.

Cardiac Allograft Vasculopathy

CAV is a major cause of morbidity and mortality following heart transplantation. The precise molecular mechanism for the development of vasculopathy is not known. Both immune and nonimmune mechanisms have been implicated in the progression of vasculopathy. Recent studies have focused on different markers related to the extracellular matrix, renin-angiotensin system, fibrinolytic system, adhesion receptors, and markers of inflammation. Angiographic evidence of transplant vasculopathy is seen in 50% to 60% of transplant recipients by 5 years. However, intravascular ultrasound (IVUS) can detect an abnormal coronary intimal thickness in 50% of patients as early as 1 year after cardiac transplantation (Fig. 3). Thus far, the improvements in immunosuppression have not greatly affected the incidence and morbidity associated with CAV development. Various risk factors have been identified for the development of CAV, including donor age, presence of coronary artery disease before transplantation, diabetes mellitus, hypertension, hyperlipidemia, frequency and type of rejection, degree of human leukocyte antigen (HLA) matching, and cytomegalovirus (CMV) infection.

The clinical manifestation of CAV early after transplantation may be silent, occurring as acute myocardial infarction, congestive heart failure, arrhythmias, wall motion abnormalities, or sudden death. Later, typical angina pectoris can occur because of focal, albeit incomplete, reinnervation. Most CAV is diagnosed by routinely scheduled yearly surveillance angiography, although many noninvasive techniques have been evaluated in an attempt to decrease the need for invasive testing. Several studies have explored the role of dobutamine stress echocardiography (DSE) in the detection of coronary vasculopathy. Regional myocardial dysfunction as assessed by DSE was associated with moderate to severe coronary intimal thickening. DSE was also shown to have a significant value in predicting outcome and prognosis following transplantation. The use of thallium-201 (201Tl) imaging has been advocated for the diagnosis of post-transplantation coronary vasculopathy, but its role remains questionable.

The treatment of established CAV appears to be limited to retransplantation and revascularization techniques, because augmented immunosuppression has not been conclusively shown to prevent progression. Retransplantation for CAV can, if performed years after the initial transplantation, result in survival rates of almost 80% at 1 year after retransplantation.

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Post-transplantation Complications

Although the patient’s primary problem of heart failure is alleviated by a successful transplant, a new set of potential long-term complications may emerge, primarily related to the effects of chronic immunosuppression.

Infectious Complications

Infection is common in organ transplant recipients. The types of infections expected in cardiac transplant recipients vary, depending on the time from transplantation. This is because the intensity of immunosuppression administered varies directly with the propensity for rejection, and the propensity to reject decreases over time. Bacteria and viruses account for more than 80% of infections after transplantation. The most common bacterial infections early after transplantation are nosocomial, caused by infected intravascular catheters or lines, or gram-negative pneumonias. The most common viral infections are caused by the herpesviruses: CMV, herpes zoster, and herpes simplex. Although CMV infection used to be associated with significant morbidity and mortality, the use of ganciclovir has significantly improved the prognosis. The overall incidence of infection is approximately 0.5 infections per patient, although as many as two thirds of patients remain free from serious infections during the first year. Given the potential morbidity and mortality associated with infections during the first post-transplantation year, infection prophylaxis is common (Table 5).

Table 5 Infection Prophylaxis After Cardiac Transplantation
Organism Regimen
Cytomegalovirus (recipient seropositive) Ganciclovir, 5 mg/kg IV bid for 2-4 wk, then 1000 mg PO tid until 1 mo post-transplantation, then acyclovir, 800 mg PO qd until 2-3 mo post-transplantation
Cytomegalovirus (recipient seronegative and donor seropositive) Ganciclovir, 5 mg/kg IV bid for 2-4 wk, then 1000 mg PO tid until 3 mo post-transplantation
Herpes simplex virus Acyclovir, 200 mg PO qd until prednisone dosage < 20 mg/day
Epstein-Barr virus (recipient seronegative and donor seropositive) Acyclovir, 800 mg PO qd for 12 mo, then 200 mg PO qd
Toxoplasma gondii (donor or recipient seropositive) Pyrimethamine, 25 mg PO qd for 6 wk and leucovorin calcium, 5-10 mg PO qd for 6 wk
Pneumocystis carinii Trimethoprim-sulfamethoxazole, 160 mg-800 mg PO 3-7 times/wk or dapsone, 75-100 mg PO qd if sulfa allergic
Candida albicans Nystatin, 10 mL swish and swallow qd, or clotrimazole troche, PO qd until prednisone dosage < 20 mg/day

Diabetes Mellitus

Although almost 20% of cardiac transplant survivors develop overt diabetes within the first year, by 5 years after transplantation, only 15% would be classified as diabetic. This is likely related to the use of decreasing dosages of corticosteroids. No evidence exists that cardiac transplant recipients should be managed differently in terms of target levels of blood glucose and glycosylated hemoglobin, or the agents used to treat them.

Hypertension

Hypertension developing after cardiac transplantation is almost universal, occurring in 70% to 90% of cyclosporine-treated and 30% to 50% of tacrolimus-treated patients. This challenging complication reflects the interplay of several pathogenic mechanisms, including altered renal vascular reactivity and sympathetic neuroactivation. Corticosteroids play a minor role in the pathogenesis of cardiac transplantation hypertension, which is described as a salt-sensitive type. Abnormal cardiorenal reflexes secondary to cardiac denervation may contribute to salt-sensitive hypertension and fluid retention.

Generally, blood pressures consistently higher than 140/90 mm Hg should be treated. Titrated monotherapy with angiotensin- converting enzyme (ACE) inhibitors or calcium channel blockers may be effective in about 50% of patients. Some patients are prone to hyperkalemia because of the combined effect of cyclosporine and ACE inhibition. Because of decreased metabolism of cyclosporine, the use of diltiazem and verapamil necessitates the use of lower doses of cyclosporine and, initially, more frequent monitoring of cyclosporine level. Combination therapy with both an ACE inhibitor and a calcium channel blocker is a commonly used strategy. Problematic hypertensives requiring multiple agents often require diuretics as parts of their regimen. Hypertension in some patients is inadequately controlled despite maximally tolerated doses of calcium channel blockers and ACE inhibitors. The final tier of management is to add clonidine, doxazosin, or minoxidil in refractory cases. Beta blockers are usually avoided in the treatment of hypertension because of their known tendency to reduce exercise performance in heart transplant recipients.

Renal Dysfunction

Immunosuppressive therapy with cyclosporine has improved both graft function and survival in heart transplantation. However, cyclosporine-induced nephrotoxicity still remains a serious clinical challenge. Chronic cyclosporine nephrotoxicity is characterized by a decrease in glomerular filtration rate (GFR), afferent arteriolopathy, and striped tubulointerstitial fibrosis. The greatest decline in GFR with cyclosporine occurs in the first 3 to 6 months. In a study of 2088 Medicare beneficiaries, the annual risk of end-stage renal disease was reported to be 0.37% in the first year after transplantation, increasing to 4.49% by the sixth post-transplantation year.

Tacrolimus (FK 506) causes functional and structural abnormalities similar to those caused by cyclosporine. The central mechanism involved is a result of inhibition of calcineurin, which may explain in part the increased systemic vascular resistance because of effects on vascular smooth muscle and indirect effects mediated by increased sympathetic neuroactivation.

Close monitoring of tacrolimus and cyclosporine blood levels is critically important to limit progressive decline in renal function, because there is no known treatment for preventing or reversing nephrotoxicity. At the time of transplantation, initiation of tacrolimus or cyclosporine is delayed postoperatively in patients at high risk for nephrotoxicity, and cytolytic induction therapy (such as monoclonal OKT3 or antithymocyte globulin [Thymoglobulin]) is used for renal-sparing purposes.

Osteoporosis

Cardiac transplantation, with its attendant glucocorticoids and calcineurin inhibitors (cyclosporine and tacrolimus), is associated with rapid bone loss (up to 35% of patients during the first year). Within 2 months after heart transplantation, approximately 3% of whole-body bone mineral density is lost, mostly because of decreases in trabecular bone. Glucocorticoids cause dose-related bone loss, particularly in the first 6 to 12 months. Cardiac transplant recipients lose bone immediately after transplantation at the spine and hip.

The treatment of osteoporosis in heart transplant patients should be directed toward preventing bone loss. Because of the morbidity associated with osteoporosis, patients at highest risk should be treated even before transplantation. Prophylactic administration of calcium carbonate and vitamin D after cardiac transplantation is an effective regimen that reduces bone loss and may decrease osteoporotic complications.

Hyperlipidemia

Hyperlipidemia is one of the most common metabolic disorders after heart transplantation, occurring in 60% to 80% of recipients. It is multifactorial in origin and may be related to preexisting lipid abnormalities, cyclosporine therapy, and corticosteroids. Corticosteroid withdrawal has been associated with lower cholesterol levels.

Coronary vasculopathy has emerged as the main determinant of long-term survival in cardiac transplant recipients. There is controversy as to whether hypercholesterolemia is an important risk factor of allograft vasculopathy. A more consistent observation has been made that an elevated plasma triglyceride level is associated with the development of coronary vasculopathy. Most likely, immune and ischemic mechanisms of endothelial injury in the setting of hyperlipidemia are likely to play a role in the development of coronary vasculopathy.

Lipid-lowering therapy using gemfibrozil, targeted to the modification of triglyceride levels, appears to confer a survival benefit in cardiac transplant recipients beyond the first year. Moderate to severe hypercholesterolemia generally requires the use of a statin agent. In a prospective randomized trial investigating pravastatin use early after heart transplantation, it was observed that pravastatin-treated patients have a decreased incidence of clinically severe acute rejection episodes, resulting in a significant improvement in 1-year survival (94% vs. 78% in the control group; P = .02). Follow-up at 5 years has shown continued survival benefit in patients receiving pravastatin (83% vs. 62%). A similar survival benefit result has been observed in a randomized prospective trial with simvastatin. This observed survival benefit probably is a class effect that is shared among all statins. The combination of cyclosporine and a statin increases the risk of rhabdomyolysis over that of a statin alone. Combining lovastatin and gemfibrozil can also predispose to rhabdomyolysis. This combination in general should be avoided. It is thus recommended that periodic creatine kinase and liver enzyme determinations be performed in all transplant recipients receiving statin agents.

Gout

Gouty arthritis is the most common rheumatologic complication among cyclosporine-treated organ transplant recipients. Preexisting gout is observed in 6% of patients before transplantation. Following heart transplantation, gouty arthritis is observed with increasing frequency in 8% to 17% of patients. It is usually polyarticular in nature and often exhibits an accelerated clinical course, with management complicated by the patient’s renal insufficiency and interaction with transplant-related medications.

Colchicine is generally effective in treating acute gouty episodes and providing prophylaxis against recurrent episodes. However, cardiac transplant recipients treated with cyclosporine may be at increased risk of developing acute colchicine-induced myoneuropathy, especially in the setting of concurrent renal insufficiency. If colchicine is administered, the dose should be reduced, cyclosporine levels monitored closely, and patients evaluated for signs of neuromuscular toxicity.

Another potential life-threatening drug interaction is the combination of allopurinol and azathioprine, resulting in pancytopenia. Because allopurinol blocks the xanthine oxidase pathway by which azathioprine is metabolized, potentially toxic levels of azathioprine can result. Mycophenolate mofetil metabolism does not involve the xanthine oxidase pathway, but it may be used safely in combination with allopurinol.

Corticosteroids may be the most effective and safest approach in the management of gout in patients with renal dysfunction. As a general rule, nonsteroidal anti-inflammatory drugs are not used because of their propensity to precipitate acute cyclosporine-induced renal toxicity.

Malignancy

Following heart transplantation, malignancy is identified in 3% to 18% of the recipients, with an estimated risk of 1% to 2% per year. It ranks second to coronary vasculopathy as a major cause of mortality, accounting for 10% to 23% of all deaths following heart transplantation. Cutaneous malignancy is the most common type, seen in up to 17% of patients, with a predominance of squamous cell carcinoma.

Post-transplantation lymphoproliferative disorder (PTLD) is a frequently fatal complication, occurring in 1.7% to 6% of cardiac transplant recipients. The peak occurrence of PTLD is 3 to 4 months after transplantation. A strong association of PTLD with Epstein-Barr virus has been observed in several series. The use of OKT3, which may favorably affect the rejection rate, has been shown to increase the risk of lymphoma more than eightfold. This association remains contentious and has been challenged.

The initial management of PTLDs usually involves reduction in immunosuppression, which may be effective in some cases. Nonresponsive patients may require aggressive combination chemotherapy, and mortality of approximately 80% has been reported in these patients.

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Retransplantation

Many ethical and fiscal issues have been raised concerning the allocation of a scarce organ to a retransplant candidate, who is 20% less likely to survive 1 year after transplantation than a primary candidate. Hence, there is the need for rigorous criteria to select the ideal candidate for retransplantation.

Coronary vasculopathy constitutes the main cause of graft failure, and the most common reason to consider retransplantation, followed by rejection and primary graft failure. Defining the ideal candidate poses a challenging therapeutic dilemma to the transplantation team, and it may not be an easy task to accomplish because of the worldwide shortage of organ donor supply. However, based on the results of some of the major transplant centers’ experiences, cardiac retransplantation may be a viable therapeutic strategy for select patients with severe coronary artery disease as the cause of allograft dysfunction. Excluding patients with intractable rejection, primary graft failure, and renal dysfunction may improve survival outcome.

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Role Of The Primary Care Physician

Successful long-term care of the transplanted heart is a team effort by the patient, transplantation team, and primary care physician. A knowledge of cardiac transplantation medicine is fundamental for the primary care physician who participates in the ongoing care of the post-transplantation patient.

The primary care physician plays an important role in the management of medical problems that need long-term follow-up, such as diabetes, hypertension, hyperlipidemia, and osteoporosis. Post-transplantation complications such as infection, rejection, coronary vasculopathy, and malignancy pose major threats to the transplanted organ and therefore require a heightened awareness by the primary care physician and appropriate referral to the cardiac transplantation team.

The long-term management of heart transplant patients is continuously evolving with the emergence of new immunosuppressive agents. The key to the safe handling of these agents by the primary care physician requires knowledge of pharmacology, including side effects and various drug-drug interactions. It is recommended that any new medications be given in consultation with the transplantation center. Appropriate antibiotic endocarditis prophylaxis is recommended for cardiac transplant recipients undergoing dental, genitourinary, or gastrointestinal procedures.

Post-transplantation psychological issues are important and often can be addressed by the primary care physician, with appropriate counseling. Hence, the primary care physician assumes a vital role in the management of cardiac transplant patients, and the demand for care continues to grow with the expanding population of long-term heart transplant recipients.

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Summary

  • Cardiac transplantation has emerged as a viable therapeutic strategy for select patients with end-stage heart disease, offering extended survival and improved quality of life.
  • The current survival rate after heart transplantation has been reported as approximately 50% at 12 years by the International Society for Heart and Lung Transplantation (ISHLT) registry.
  • The paucity of the donor pool demands a careful patient selection process to ensure appropriate candidacy.
  • Patients are listed according to their medical urgency status and severity of their illness.
  • Post-transplantation complications include acute rejection, infection, transplant vasculopathy, metabolic complications, renal insufficiency, bone diseases, and malignancy.
  • Successful long-term care of the transplanted heart is a team effort by the patient, transplantation team, and primary care physician.

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Suggested Readings

  • Kirklin JK, Pambukian SV, McGiffin DC, Benza RL: Current outcomes following heart transplantation. Semin Thorac Cardiovasc Surg 2004;16:395-403.
  • Lindenfeld JA, Miller GG, Shakar SF, et al: Drug therapy in the heart transplant recipient. Part I: Cardiac rejection and immunosuppressive drugs. Circulation 2004;110:3734-3740.
  • Lindenfeld JA, Miller GG, Shakar SF, et al: Drug therapy in the heart transplant recipient. Part II: Immunosuppressive drugs. Circulation 2004;110:3858-3865.
  • Mehra MR, Uber PA, Uber WE, et al: Allosensitization in heart transplantation: Implications and management strategies. Curr Opin Cardiol 2003;18:153-158.
  • Sharples LD, Caine N, Mullins P, et al: Risk factor analysis for the major hazards following heart transplantation-rejection, infection, and coronary occlusive disease. Transplantation 1991;52:244-252.
  • Steward S, Winters GL, Fishbein MC, 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.
  • Taylor DO, Edwards LB, Boucek MM, et al: Registry of the International Society for Heart and Lung Transplantation: Twenty-fourth official adult heart transplant report—2007. J Heart Lung Transplantation 2007:26(8):769-781.
  • Yamani MH, Starling RC: Long-term management issues in heart transplantation. In Norman DJ, Turka LA (eds): Primer on Transplantation, 2nd ed. Mt. Laurel, NJ, American Society of Transplant, 2001, pp 375-381.
  • Yamani MH, Starling RC: Surrogate markers of transplant vasculopathy. Curr Opin Organ Transplant 2004;9:443-447.
  • Young JB, Winters WL Jr, Bourge R, Uretsky BF: 24th Bethesda Conference: Cardiac transplantation. Task Force 4: Function of the heart transplant recipient. J Am Coll Cardiol 1993;22:31-41.

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