Clinical aspects of heart transplantation

The aim of this thesis is to describe the continued efforts to optimize patient care by ongoing analysis of various problems which currently predominate in bean transplantation. Chapters l-ID describe our research in heart transplant candidates and in subsequent chapters specific problems of the transplant recipient are addressed. Attempts to reduce the incidence of rejection are described in Chapters IV and V. The problems of coronaty vascular disease in the allograft and the angiographic findings in our patients are summarized in Chapters VI, VII and VID. The complications of immunosuppressive therapy are subject of Chapters IX, X and XI.Finally, the results in the first 200 heart transplant recipients of the Rotterdam Hea.rt Transplant Program are presented in Chapter XII

Peripheral monitoring of direct and indirect alloantigen presentation pathways in clinical heart transplant recipients

It has been reported that the response to alloantigens presented by the direct and indirect pathway may be of differential relevance after human kidney transplantation. Accordingly, we monitored these routes in peripheral blood mononuclear cells (PBMC) of heart transplant patients from before transplantation and up to 2 years thereafter in an attempt to find a correlation with the clinical status of the patients. Both before and after transplantation, comparable proportions of PBMC samples reacted in mixed lymphocyte culture to nondepleted donor spleen cells (direct route), but never to donor cells depleted for antigen-presenting cells (indirect route). In contrast, the latter route could easily be activated by a nominal antigen and persisted after transplantation, although the proportion of PBMC samples responding was significantly suppressed, irrespective of the occurrence of rejection. Consequently, complete removal of antigen-presenting cells from the stimulator population in a mixed lymphocyte culture with PBMC as responder is not a suitable tool for measuring indirect presentation of alloantigens, and therefore not relevant for monitoring the immunological status of heart transplant recipients

Characteristics of graft-infiltrating lymphocytes after human heart transplantation: HLA mismatches and the cellular immune response within the transplanted heart

The influence of HLA mismatches between donor and recipient on the phenotypes, function, and specificity of T-lymphocyte cultures derived from endomyocardial biopsies was studied in 118 heart transplant recipients. In case of HLA-DR mismatches, the majority of the EMB-derived cultures were dominated by CD4+ T cells while, in patients with HLA-A and -B mismatches but without DR mismatches, CD8+ T cells comprised the predominant T-cell subset. Cytotoxicity against donor antigens was observed in 75% of the cultures. A significantly (p < 0.005) lower proportion of the cultures showed cytotoxicity against HLA-A antigens (36%) when compared with HLA-B (53%) or HLA-DR (49%). An HLA-A2 mismatch elicited a cytotoxic response that was comparable to that found against HLA-B and -DR antigens: 62% of the cultures from HLA-A2 mismatched donor-recipient combinations was reactive against A2. A higher number of A, B, or DR mismatches resulted in a higher number of cytotoxic cultures directed against these antigens. A higher number of HLA-B and -DR mismatches was associated with a lower freedom from rejection. Our data indicate that, despite the use of adequate immunosuppressive therapy, the degree of HLA matching plays a crucial role in the immune response against a transplanted heart, resulting in a significant effect on freedom from rejection

Collagen content and distribution in the normal and transplanted human heart: A postmortem quantitative light microscopic analysis

Endomyocardial biopsies in heart transplant patients offer the opportunity to study the myocardial interstitium in the context of myocardial function. For that purpose endomyocardial biopsies should reliably reflect the composition of the entire myocardium. We determined whether the collagen content in the subendocardial region of the right side of the interventricular septum (site of right ventricular endomyocardial biopsy), in 16 normal and 30 transplanted human hearts, is representative for the entire myocardium. Moreover we determined whether or not the mean collagen content of the myocardium is altered along with the posttransplantation survival time and which factors might contribute to the development of interstitial myocardial fibrosis. Transmural sections of the right and left ventricular free wall and interventricular septum were stained with Sirius red, which specifically stains collagen fibers. Collagen in the subendocardial region and central parts of the myocardium was quantified using a digital image analyzer. In normal hearts the mean collagen content of the subendocardial region of the right side of the interventricular septum (site of right ventricular endomyocardial biopsy) correlates well with the mean collagen content of the right ventricular wall and the center of the interventricular septum, but it does not reliably reflect the mean collagen content of the left ventricular free wall. In transplanted hearts the collagen content at the site of right ventricular endomyocardial biopsy correlates highly with the mean collagen content of the entire myocardium. In transplanted hearts the increase in collagen content is a result mainly of an increase in collagen of the left ventricular free wall. We conclude that in heart transplant patients, right ventricular endomyocardial biopsies have potential value in the analysis of the causes of left ventricular dysfunction. In transplanted human hearts, the posttransplantation survival time correlates positively with the collagen content, and this is attributable mainly to an increase in the collagen of the left ventricular free wall

Intragraft interleukin 2 mRNA expression during acute cellular rejection and left ventricular total wall thickness after heart transplantation

OBJECTIVE: To assess whether diastolic graft function is influenced by intragraft interleukin 2 (IL-2) messenger RNA (mRNA) expression in rejecting cardiac allografts. DESIGN: 16 recipients of cardiac allografts were monitored during the first three months after transplantation. The presence of IL-2 mRNA in endomyocardial biopsies (n = 123) was measured by reverse transcriptase polymerase chain reaction. To determine heart function, concurrent M mode and two dimensional Doppler echocardiograms were analysed. RESULTS: Histological signs of acute rejection (International Society for Heart and Lung Transplantation (ISHLT) rejection grade > 2) were strongly associated with IL-2 mRNA expression (IL-2 mRNA was present in 12 of 20 endomyocardial biopsies (60%) with acute rejection and in 24 of 103 endomyocardial biopsies (23%) without acute rejection, p = 0.002). No significant relation was found between either histology or IL-2 mRNA expression alone and the studied echocardiographic parameters. However, stratification of the echocardiographic data into those of patients with and those without acute rejection showed that during acute rejection IL-2 mR