Burden of myocardial damage in cardiac allograft rejection: Scintigraphic evidence of myocardial injury and histologic evidence of myocyte necrosis and apoptosis

Background. Because myocardial damage determines morbidity and outcomes in heart transplant rejection, assessment of total burden of myocardial damage is highly desirable, In addition to myocyte necrosis, programmed cell deat h, or apoptosis, has recently been shown to contribute to cardiac allograft rejection. In the present study, we noninvasively determined myocardial da mage by antimyosin scintigraphy and compared it with necrotic and apoptotic myocardial damage in endomyocardial biopsy (EMB) specimens. Methods and Results. Forty scintigraphic and histologic studies were simult aneously performed. Of these, 19 patients had no EMB evidence of allograft rejection (group I, International Society of Heart and Lung Transplantation [ISHLT] grade 0/4), 12 had mild rejection (group II, ISHLT grades 1A and 1 B), and 9 had evidence of moderate allograft rejection (group III, ISHLT gr ades 2, 3A, and 3B), None of the biopsies demonstrated severe allograft rej ection (ISHLT grade 4/4), The severity of global myocyte damage in 40 patie nts was assessed by antimyosin scintigraphy, Endomyocardial biopsies were p erformed in these patients within 48 hours of imaging study; biopsy specime ns were characterized for presence of myocyte necrosis and apoptosis, Evide nce of myocyte necrosis was observed in 9 (23%) of 40 EMB specimens, Ninete en EMB specimens of group I had no inflammation and no myocyte necrosis, 12 of group II specimens showed interstitial mononuclear cell infiltration (o nly) but no myocyte necrosis, and all 9 of group III specimens had evidence of cellular infiltration and myocyte damage. Myocyte necrosis was assessed by hematoxylin-eosin and trichrome staining of EMB specimens. On the other hand, apoptosis of myocytes, as assessed by TUNEL staining of DNA fragment s, was seen in 22 (55%) of the 40 biopsy specimens: 47%, 58%, and 67% in gr oups I, II and III, respectively. Abnormal antimyosin scan findings, indica ting presence of myocardial damage, were observed in 9 of the 19 patients i n group I and in all patients in groups II and III. Although positive antim yosin scan results in group III patients are concordant with the presence o f histologic myocardial necrosis, myocardial uptake of antimyosin antibodie s in groups I and II (no apparent myocyte damage at light microscopic exami nation) could reflect either sampling error of the biopsy or ongoing apopto tic myocyte damage. Conclusions, Apoptosis of myocytes is frequently observed during cardiac al lograft rejection. The presence of apoptotic myocytes in the absence of his tologic rejection activity in patients with antimyosin uptake suggests that apoptosis could be an additional mechanism of transplant-associated myocar dial damage.