Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara J A, Quaini E, Di Loreto C, Beltrami C A, Krajewski S, Reed J C, Anversa P
Department of Medicine, New York Medical College, Valhalla 10595, USA.
N Engl J Med. 1997 Apr 17;336(16):1131-41. doi: 10.1056/NEJM199704173361603.
Loss of myocytes is an important mechanism in the development of cardiac failure of either ischemic or nonischemic origin. However, whether programmed cell death (apoptosis) is implicated in the terminal stages of heart failure is not known. We therefore studied the magnitude of myocyte apoptosis in patients with intractable congestive heart failure.
Myocardial samples were obtained from the hearts of 36 patients who underwent cardiac transplantation and from the hearts of 3 patients who died soon after myocardial infarction. Samples from 11 normal hearts were used as controls. Apoptosis was evaluated histochemically, biochemically, and by a combination of histochemical analysis and confocal microscopy. The expression of two proto-oncogenes that influence apoptosis, BCL2 and BAX, was also determined.
Heart failure was characterized morphologically by a 232-fold increase in myocyte apoptosis and biochemically by DNA laddering (an indicator of apoptosis). The histochemical demonstration of DNA-strand breaks in myocyte nuclei was coupled with the documentation of chromatin condensation and fragmentation by confocal microscopy. All these findings reflect apoptosis of myocytes. The percentage of myocytes labeled with BCL2 (which protects cells against apoptosis) was 1.8 times as high in the hearts of patients with cardiac failure as in the normal hearts, whereas labeling with BAX (which promotes apoptosis) remained constant. The near doubling of the expression of BCL2 in the cardiac tissue of patients with heart failure was confirmed by Western blotting.
Programmed death of myocytes occurs in the decompensated human heart in spite of the enhanced expression of BCL2; this phenomenon may contribute to the progression of cardiac dysfunction.
心肌细胞丢失是缺血性或非缺血性心力衰竭发生发展的重要机制。然而，程序性细胞死亡（凋亡）是否参与心力衰竭的终末期尚不清楚。因此，我们研究了顽固性充血性心力衰竭患者心肌细胞凋亡的程度。
从36例接受心脏移植患者的心脏以及3例心肌梗死后不久死亡患者的心脏获取心肌样本。11例正常心脏的样本用作对照。通过组织化学、生物化学以及组织化学分析与共聚焦显微镜相结合的方法评估凋亡情况。还测定了两种影响凋亡的原癌基因BCL2和BAX的表达。
心力衰竭在形态学上的特征是心肌细胞凋亡增加232倍，在生物化学上的特征是出现DNA梯状条带（凋亡的一个指标）。心肌细胞核中DNA链断裂的组织化学证明与共聚焦显微镜下染色质浓缩和断裂的记录结果相符。所有这些发现均反映了心肌细胞的凋亡。用BCL2（保护细胞免于凋亡）标记的心肌细胞百分比在心力衰竭患者心脏中是正常心脏的1.8倍，而用BAX（促进凋亡）标记的情况保持不变。心力衰竭患者心脏组织中BCL2表达几乎翻倍通过蛋白质印迹法得到了证实。
尽管BCL2表达增强，但失代偿的人心脏中仍会发生心肌细胞程序性死亡；这种现象可能导致心脏功能障碍的进展。
