Puig M, Ballester M, Matías-Guiu X, Bordes R, Carrió I, Kolodgie F D, Pons C, García A, Aymat M R, Marrugat J, Brossa V, Campreciós M, Padró J M, Caralps J M, Virmani R, Prat J, Narula J
Cardiomyopathy and Heart Transplantation Program, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
J Nucl Cardiol. 2000 Mar-Apr;7(2):132-9. doi: 10.1016/s1071-3581(00)90033-3.
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 death, or apoptosis, has recently been shown to contribute to cardiac allograft rejection. In the present study, we noninvasively determined myocardial damage by antimyosin scintigraphy and compared it with necrotic and apoptotic myocardial damage in endomyocardial biopsy (EMB) specimens.
Forty scintigraphic and histologic studies were simultaneously 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 1B), and 9 had evidence of moderate allograft rejection (group III, ISHLT grades 2, 3A, and 3B). None of the biopsies demonstrated severe allograft rejection (ISHLT grade 4/4). The severity of global myocyte damage in 40 patients was assessed by antimyosin scintigraphy. Endomyocardial biopsies were performed in these patients within 48 hours of imaging study; biopsy specimens were characterized for presence of myocyte necrosis and apoptosis. Evidence of myocyte necrosis was observed in 9 (23%) of 40 EMB specimens. Nineteen EMB specimens of group I had no inflammation and no myocyte necrosis, 12 of group II specimens showed interstitial mononuclear cell infiltration (only) 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 fragments, was seen in 22 (55%) of the 40 biopsy specimens: 47%, 58%, and 67% in groups I, II and III, respectively. Abnormal antimyosin scan findings, indicating presence of myocardial damage, were observed in 9 of the 19 patients in group I and in all patients in groups II and III. Although positive antimyosin scan results in group III patients are concordant with the presence of histologic myocardial necrosis, myocardial uptake of antimyosin antibodies in groups I and II (no apparent myocyte damage at light microscopic examination) could reflect either sampling error of the biopsy or ongoing apoptotic myocyte damage.
Apoptosis of myocytes is frequently observed during cardiac allograft rejection. The presence of apoptotic myocytes in the absence of histologic rejection activity in patients with antimyosin uptake suggests that apoptosis could be an additional mechanism of transplant-associated myocardial damage.
由于心肌损伤决定了心脏移植排斥反应的发病率和预后，因此对心肌损伤的总负担进行评估非常必要。除了心肌细胞坏死外，程序性细胞死亡或凋亡最近已被证明与心脏移植排斥反应有关。在本研究中，我们通过抗肌凝蛋白闪烁显像术无创地测定心肌损伤，并将其与心内膜心肌活检（EMB）标本中的坏死和凋亡性心肌损伤进行比较。
同时进行了40项闪烁显像和组织学研究。其中，19例患者的EMB检查未发现移植排斥反应的证据（第一组，国际心肺移植学会[ISHLT]0/4级），12例有轻度排斥反应（第二组，ISHLT 1A和1B级），9例有中度移植排斥反应的证据（第三组，ISHLT 2、3A和3B级）。所有活检均未显示严重移植排斥反应（ISHLT 4/4级）。通过抗肌凝蛋白闪烁显像术评估了40例患者的整体心肌细胞损伤严重程度。在影像学研究的48小时内对这些患者进行了心内膜心肌活检；对活检标本进行了心肌细胞坏死和凋亡的特征分析。在40例EMB标本中的9例（23%）观察到心肌细胞坏死的证据。第一组的19例EMB标本无炎症且无心肌细胞坏死，第二组的12例标本仅显示间质单核细胞浸润但无心肌细胞坏死，第三组的所有9例标本均有细胞浸润和心肌细胞损伤的证据。通过苏木精-伊红和三色染色对EMB标本评估心肌细胞坏死。另一方面，通过DNA片段的TUNEL染色评估，40例活检标本中有22例（55%）出现心肌细胞凋亡：第一组、第二组和第三组分别为47%、58%和67%。在第一组的19例患者中有9例以及第二组和第三组的所有患者中均观察到抗肌凝蛋白扫描结果异常，表明存在心肌损伤。虽然第三组患者抗肌凝蛋白扫描结果阳性与组织学心肌坏死的存在一致，但第一组和第二组（在光学显微镜检查下无明显心肌细胞损伤）抗肌凝蛋白抗体的心肌摄取可能反映活检的抽样误差或正在进行的凋亡性心肌细胞损伤。
在心脏移植排斥反应期间经常观察到心肌细胞凋亡。在抗肌凝蛋白摄取的患者中，在无组织学排斥活动的情况下存在凋亡性心肌细胞表明凋亡可能是移植相关心肌损伤的另一种机制。
