New methods for noninvasive monitoring of rejection after heart transplantation

Between August 1981 and February 1987, 67 orthotopic heart transplants and three heart-lung transplants were performed in 69 patients at the University of Munich Hospital. The immunosuppressive regimen consisted of cyclosporine A, azathioprine, and prednisone. The diagnosis of acute rejection was based on cytoimmunologic monitoring, frequency analysis of fast Fourier transformed surface electrocardiograms (FFT-ECGs), and two dimensional echocardiography. The results of these diagnostic methods were compared to the findings provided by endomyocardial biopsies, which were performed simultaneously with the noninvasive studies. Seventy patients underwent cytoimmunologic monitoring. In 88% of all rejection episodes, this technique revealed activated lymphocytes and lymphoblasts in the mononuclear concentrate of the peripheral blood samples; the presence of such cells is known to be an extremely early sign of acute rejection. Twenty-six patients were monitored by means of FFT-ECG. In 20 of the 21 cases of rejection, this method disclosed significant changes in the frequency spectrum of the QRS complex in the 70- to 110-Hz range; in 12 cases, these changes were the earliest sign of acute rejection. Therefore, FFT-ECG had a sensitivity of 95%. All of the QRS changes were reversible with rejection therapy. Forty-five patients were subjected to two-dimensional echocardiography. In 31 of the 35 cases of rejection, the echocardiogram showed a significant increase in the left ventricular wall thickness and a decrease in the left ventricular cross-sectional area during mild rejection. Moderate or severe rejection was characterized by an increase in the diastolic area, as well as a decrease in the systolic area change and in the diastolic maximum velocity of area change. Thus, two-dimensional echocardiography had a sensitivity of 89%. In the recent cases, the diagnosis of rejection was based on noninvasive methods alone. After rejection therapy had been instituted, endomyocardial biopsies were performed to assess the effectiveness of the treatment. With noninvasive rejection monitoring, the number of endomyocardial biopsies performed during the first three postoperative months was only 2.8 per patient; in comparison with invasive rejection monitoring, noninvasive follow-up was associated with a 75% reduction in the need for biopsy.