Back to CARDIOLOGYOver the past decade heart transplantation ( HT ) has evolved from a rarely performed procedure to an accepted therapy for advanced heart failure. The need for HT as a therapeutic option is underscored by some important facts regarding heart failure. It is estimated that each year 40.000 patients with heart failure progress to end-stage disease. Drugs that improve heart failure outcome have decreased short and medium-term mortality by an average of only 20 %. The 3 to 4 year mortality and hospitalization rates remain 50 % even in patients treated with the best drugs available. Hence the need to offer heart failure patients nonpharmacologic measures.
After a sharp increase in the number of procedures during the mid 1980s, during the past 5 years the number has remained static and has not exceeded 3500 per year worldwide. The stunted growth of HT procedures is due to a critical donor shortage. Since 1987, when the United Network for Organ Sharing ( UNOS ) began operating, the supply of donor organs has not kept pace with demand, and the discrepancy between the number of donor organs available and the number of HT candidates continues to widen. In fact, the modest increase in the number of organ donors reported in recent years by UNOS is entirely attributable to the acceptance of increasingly older donors.
The most important task of heart failure specialists is to select the patients most likely to derive the greatest benefit from the procedure and, at the same time, who are at the highest risk of death without HT. To successfully acomplish the difficult task of candidate selection, it is critical to exclude the presence of reversible causes of heart failure in each and every patient referred for HT. In the absence of reversible causes, physicians must then weigh the relative risk of coexisting morbidities, keeping in mind that the risk of a poor outcome after HT increases continuously with each comorbid condition and may be additive. The next step is to predict the patients' prognosis based on clinical, functional, neurohormonal and arrhytmic variables. When doing so, some important guidelines should be followed . First, prognostic variables should be measured only after therapy has been optimized. Second, variables such as New York Heart Association functional class and left ventricular ejection fraction loose their discriminatory power in patients with advanced heart failure. Third, the prognosis of patients with advanced disease should be predicted as much as possible on the basis of objective criteria, such as peak exercise oxygen consumption ( VO2 max ) and determination of plasma norepinephrine levels. The measurement of VO2 max. has been a useful supplementary criterion not only for the selection of patients for HT but also for its timing. Maximal exercise performance exceding 14ml/kg/min predicted a 1 year survival of greater than 90 % ( which is higher than 1 year survival after HT, so that it can be safely postponed ). The worst outlook was for those patients whose peak VO2 was < 10ml/kg/min, and they, if otherwise acceptable, should undergo HT. Those with intermediate variables require additional evaluation based on disability, quality of life and age.
If these variables predict a poor outcome despite optimal medical therapy, the next step in the process of selection is evaluation of the presence and reversibility of pulmonary arterial hypertension. This is an important consideration, since orthotopic HT requires that the pulmonary vascular resistance be low, so that the normal right ventricle of the donor heart can adequately support the recipient's circulation after transplantation. In order to measure pulmonary vascular resistance, most HT programs use the measurement of the traditional Wood unit, the limit value being of < 6units at rest or < 3 with maximal vasodilation. Other centers use either the pulmonary vascular resistance index ( corrected for body surface area ) or the transpulmonary pressure gradient ( mean pulmonary artery minus mean pulmonary cappilary wedge pressure ) < 15 mmHg. Whatever measure is used, in patients with values towars the upper limits, it is imperative to demonstrate in the catheterization laboratory that the resistance can be manipulated with either oxygen or vasodilators with or without inotropic agents. If the pulmonary vascular resistance remains elevated, consideration should be given to either heterotopic HT, which leaves the recipient's heart intact, or heart-lung trasplantation. Since patients may be on a waiting list for more than six months, repeat measures may be necessary semiannualy to determine if it has increased. Significantly elevated pulmonary vascular resistance and right heart failure remain problems after orthotopic HT and are major causes of early postoperative mortality. Contraindications for HT are summarized in Table 1
According to data from the Registry of the International Society for Heart and Lung Transplantation, of the patients undergoing HT, 46.6 % have coronary artery disease and 44 % have idiopathic dilated cardiomyopathy. The remainig 9.4 % patients have valvular or congenital heart disease, allograft failure or other infrequent causes ( refractory arrhytmias, ... ).
Evaluation and Management of the Heart Donor :
The factor limiting the number of HTs performed is the availability of donor organs. Thus, it is imperative to obtain a high percentage of potential donors. Brain death has been accepted as a legal definition of death in the USA, and this diagnosis cannot involve physicians caring for the potential candidate and it requires the absence of hypothermia ( < 32.5 º C ) or drugs capable of altering neurological or neuromuscular function.
Until recently, donor criteria were very selective. The upper age limit was usually 35 years of age, and there was a number of other criteria. With the need to increase the number of transplants, most centers now evaluate any potential donor up to 55 years of age, including coronary arteriography for men older than 45 or women older than 55 years old.
The current criteria for allocation of donor hearts include priority UNOS status, ABO blood group compatibility, body size match and distance from donor center. Patients are designated status I if they require continuous inotropic and mechanical support in an intensive care unit setting ( priority for HT ); all other waiting patients are designated status II. When HT is performed across the ABO blood barrier, there is a significant risk of hyperacute rejection. With respect to size, donors who weigh less than 80 % of the recipient's weight should not be accepted for those patients who have higher levels of pulmonary vascular resistance. Similarly, hearts with ischemic times over two hours should be avoided in this situation.
Signs in brain death patients are usualy unstable and close attention is required to fluid requirements, as the pituitary gland no longer secretes vasopressin, causing diabetes insipidus. This necessitates monitoring of central venous pressure and adequate fluid ressucitation, aministration of vasopressin and replacement of fluid lost through urine output. If hypotension occurs despite adequate volume replacement, a vasopressor is infused. Dopamine is the standard inotropic agent used, but some donors will be better maintained on an alpha-adrenergic agent.
Donor evaluation also includes various serology results, as HIV, Hepatitis B and C, CMV and Toxoplasmosis.The finding of HIV antibodies rules out a potential donor, and a positive CMV serology may disqualify a potential heart-lung donor for a CMV negative recipient at some centers.
The most widely employed technique for orthotopic HT involves anastomosis of donor and recipient atria, pulmonary arteries and aortae. More recently, the bicaval anastomosis technique has been carried out at some centers. Potential advantages of this technique, which maintains the anatomic integrity of the donor right atrium, include a reduction in the incidence and severity of tricuspid regurgitation, preservation of right atrial booster pump function and facilitation of restoration of sinus rythm.
Postoprerative Care
The main problems influencing the course of HT recipients include acute allograft rejection, cardiac allograft vasculopathy ( CAV ), and infections. The risk of rejection is highest in the first 3 postoperative months, with 84 % of patients of patients using the standard triple drug therapy for imonossupression ( Prednisone, Azathioprine and Cyclosporin ) having at least one episode of rejection. However, the risk decreases dramatically within 6 months after HT. At 18 months after HT the freedom from death due to rejection is 97 %. This successful control of acute allograft rejection is due to routine rejection surveillance, standardization of rejection grading and improved imunossupression. There is still no techique with sufficient sensitivity and specificity to become an acceptable substitute for endomyocardial biopsy for detection of acute allograft rejection. Table 2 shows the recommended frequency of endomyocardial biopsy for monitoring of HT rejection.
The rejection process begins with the recognition of allograft antigens by the recipient's immunocompetent cells, which become activated and mediate allograft damage through the productin of various cytokines. The most widely used imunossuopressive agents include Cyclosporin, Azathioprine and Corticosteroids ( Table 3 ). However, a large number of new imunosupressive agents are already employed in clinical practice or are undergoing clinical trials. These include drugs that interfere with cell-to-cell signaling and adhesion, such as monoclonal antibodies, fusion molecules, drugs that inhibit cytokine synthesis ( FK 506 ) or action ( Rapamycin ), purine or pyrimidine synthesis inhibitors, and drugs that prevent maturation of already differentiated immunocompetent cells. It is important to note that the imunosupressive protocols used varie widely from center to center.
CAV is a vascular disease that affects all vessels in the transplanted heart ( includind veins ) and leads to vessel lumen obliteration. It is characterized by rapidly progressive diffuse narrowing of the coronary arteries by proliferating smooth muscle cells. Immunologic factors are thought to be involved, but increasing attention is being paid to nonimmune causes as donor ischemia time, age, gender, and preexisting coronary disease, as well as recipient's factors such as hyperlipidemia, hypertension, CMV infection and immunosupression. It is the leading cause of death after the first year of HT and the main limiting factor to the long-term survival of transplant recipients, its incidence ranging from 10-50 % at 1 year to 50-90 % at 5 years. Yearly coronary arteriography is an inadequate diagnostic method for surveillance, as shown by studies using intravascular ultrasound, and is explained by the diffuse and concentric lesion of the vascular wall. Pharmacologic and nonpharmacologic therapies of CAV are very limited. Lipid lowering therapy may be beneficial. Anticoagulation and treating hypertension are unproved measures. Angioplasty, atherectomy and surgical revascularization have been performed in recipients with discrete coronary lesions. All these procedures are palliative and have not been shown to alter the natural history of CAV. Retransplantation is the only definitive therapy for CAV, but donor shortage and lower survival ( 48 % at 1 year ) limit its usefulness.
Chronic imunosupression renders HT recipients more susceptible to infections. Of these, 46% are bacterial, 40 % viral, 7 % fungal and 5 % protozoal. The frequency of bacterial infections peak within the first month after HT, whereas the risk of viral infections is highest between the second and third month after HT. As is the case with rejection, the risk of infections sharply declines after 6 months. The most frequent sites of infection are the lung and the blood.
There are clinical issues unique to HT recipients that physicians should know so that good long term postoperative outcome can be achieved. Donor heart denervation produces an altered physiologic response to exercise and commonly used cardiovascular drugs ( eg. Beta blockers should not be used, as chronotropic function is extremely sensitive to circulating cathecolamines as there is an upregulation of receptors due to loss of symphatetic nerves ), and causes myocardial ischemia to be silent. Hypertension is almost universal, is multifactorial, and its control often requires a combination of antihypertensive drugs. Hyperlipidemia is common and should be agressively treated because it may play a role in CAV. Chronic immonosupression leads to increases risk of infections and malignancies. Because of adrenal supression caused by protracted corticosteroid use, transplant recipients should be treated with stress doses of these drugs when having a concomitant ilness or undergoing a surgical procedure. Bacterial endocarditis prophylaxis is strongly recommended for any procedure that might produce bacteremia. Vaccinations with live virus should be avoided. Finally, it is imperative to have a solid knowledge of the numerous drug interactions between immunosuppressive agents and commonly used drugs.
The above limitations of HT should not be underestimated. However, it is unquestionable that the survival rates of HT recipients are ( 1 year survival rate of 85 % and 5 year survival of 75-80 % at major centers ) higher than the survival rates afforded by optimal medical therapy to patients with heart failure of sufficient severity ( NYHA class III and IV ) to justify consideration of HT.
The future holds exciting advances for treatment of patients with advanced heart failure. These include new and more effective medical therapies and the use mechanical ( ventricular assist devices ) and biological ( xenotransplantation ) alternatives to human heart replacement. The outcome of HT may be improved by the identification of noninvasive methods for the diagnosis of rejection, the introduction of new immunosupressants, improved understanding of the pathogenesis of CAV and the induction of allograft tolerance by genetic manipulation of donor and recipient.
Back to CARDIOLOGY
Back to SPECIALTIES
Back to MEDSTUDENTS HOMEPAGE