HEART-TRANSPLANTATION - STATE-OF-THE-ART TODAY

In spite of pharmacological progress, end stage congestive heart failu re is still associated with a decrease in quality and expectation of l ife. Heart transplantation remains the last therapeutic option for the se patients. While the one year survival rate has increased over the l ast few years up to 84%, a major problem remains the significant lack of donors. Therefore, the criteria for the selection of candidates for cardiac transplantation have to be kept quite tight: Evidence of poor outcome without transplantation is associated with ejection fractions below 20 to 25%, cardiac indices less than 2,0 l/min/m(2), left ventr icular filling pressure above 20 mm Hg and a enddiastolic diameter of > 80 mm. There are, however, also quite important functional parameter s indicating the need for heart transplantation, e.g. the maximal oxyg ene uptake being less than 10 ml/kg/min or below 50% of the age-approp riate value. Elevated pulmonary vascular resistance above 4 to 5 Wood units without a significant decrease during application of prostagland in derivatives or inhalation of NO represents a contraindication for o rthotopic heart transplantation alternatively, a heterotopic transplan tation can be considered. Since there is a significant shortage of sui table donor organs, the donor criteria have been broadened, e. g. the accepted donor age was increased to 60 years. Eased on these extended criteria, a careful donor evaluation including cardiac history, cardia c examination, ECG and echocardiogram has to be performed. Coronary an giography in older donors is suggested, but in many cases not possible due to circumstances. Further precondition for a good graft function is a sophisticated donor management until the time of explantation. Hy povolemia and hypocalemia, hypothermia, hypoxia and rapid lost of circ ulating triiodothyronine (T-3) have to be detected and balanced. The c ardioplegic solution used might not only have an impact on the immedia te postoperative performance of the graft, but also on the long term o utcome, particularly with regard to graft vessel disease. There are ge nerally two types of solutions: Those with intracellular and those wit h extracellular electrolyte concentrations. In addition, the potassium concentration might be of some importance. Potassium seems to damage endothelial cells and trigger subsequent immunological reactions. Ther efore, high potassium concentrations in the cardioplegic solution migh t correlate with the incidence of graft vessel disease during the long term follow-up. The surgical technique for orthotopic heart transplan tation developed at the beginning of the sixties by Lower and Shumway has been used unchanged for the last 30 years. The only alteration rec ently introduced is the separate direct anastomosis of the pulmonary a nd systemic veins in order to improve the atrial function. Until recen tly the commonly employed immunosuppressive strategy after heart trans plantation consisted of the standard drugs cyclosporin, azathioprin an d prednisolon. Some transplant-units use additionally induction therap y with antibody preparations. Many centers, however, abolished this re gimen due to significant short and long term side effects. Promising n ew, more specific antibodies (which are chimerized or humanised) could revive the induction concept. The most thoroughly tested novel immuno suppressive agent is tacrolimus (FK506). It has been demonstrated to b e 10 to 100 times more potent than cyclosporin A in in vitro and in vi vo models. It binds to a different binding protein (FK-binding-protein ) than cyclosporin (cyclophilin), but has a similar mechanism of actio n inhibiting the expression of T-cell-activator genes for certain cyto kines. First non-randomised studies after heart transplantation perfor med at the University of Pittsburgh revealed that significantly more t acrolimus than cyclosporin patients were free of rejection. In order t o confirm these observations, we performed a prospective randomised co ntrolled clinical study. When compared to cyclosporine, tacrolimus pro ved to be a save and effective immuno-suppressant with similar surviva l rates and a significant reduction in the incidence of acute myocardi al rejection. The safety profiles of tacrolimus and cyclosporine appea red to be comparable in most major categories. Furthermore, we found t hat initial intravenous tacrolimus therapy is highly recommended in th e immediate post transplant period. Another new immunosuppressive agen t mycophenolate mofetil (MMF), a morpholinoethyl ester of mycophenolic acid, inhibits the de novo synthesis of purines and acts thus as sele ctive suppressor of the proliferation of both T- and B-lymphocytes. Ba sed on early clinical results from kidney transplantation, a multicent er trial in heart transplantation was designed comparing MMMF and azat hioprin (in combination with cyclosporine and corticosteroids) after h eart transplantation. The study indicated that patients treated with M MF have favourable survival rates. In the meantime, we combined MMF an d tacrolimus and found that the efficacy of MMF (in this combination) is highly dependent on MMF-trough levels. Therefore. we are currently adjusting the MMF dosage, targeting blood levels of 2.5 to 4 mu g/ml. To date, using this regimen, we have been able to prevent rejection af ter heart transplantation completely. The (with regard to clinical tri als) least tested major new in immunosuppressive substances is sirolim us (rapamycin). The molecule is related to tacrolimus and binds to the same protein, but acts later in the activation cascade (G1 phase of t he cell cycle). So far, sirolimus has only been used for control of re jection episodes after heart transplantation. It remains to be seen if the substance also a potent drug for primary immunosuppression after heart transplantation. Any increase of immunosuppression might also be associated with a higher risk for infections. Particularly the cytome galovirus (CMV) continues to be an important cause of infection and di sease in organ transplant recipients. Therefore, improved CMV-prophyla xis using a newly available oral formulation of gangciclovir might red uce or at least delay the onset of CMV infection. Acute rejection reac tions and infections represent the most important factors for the outc ome only within the first year after transplantation. In the late foll ow-up, however, graft vessel disease becomes the major problem in card iac recipients. It is manifested by a unique and unusually a