Frustaci A, Chimenti C, Setoguchi M, Guerra S, Corsello S, Crea F, Leri A, Kajstura J, Anversa P, Maseri A
Departments of Cardiology and Endocrinology, Sacred Heart Catholic University, Rome, Italy.
Circulation. 1999 Mar 23;99(11):1426-34. doi: 10.1161/01.cir.99.11.1426.
Prolonged untreated acromegaly leads to a nonspecific myopathy characterized by ventricular dysfunction and failure. However, the mechanisms responsible for the alterations of cardiac pump function remain to be defined. Because cell death is implicated in most cardiac disease processes, the possibility has been raised that myocyte apoptosis may occur in the acromegalic heart, contributing to the deterioration of ventricular hemodynamics.
Ten acromegalic patients with diastolic dysfunction and 4 also with systolic dysfunction were subjected to electrocardiography, Holter monitoring, 2-dimensional echocardiography, cardiac catheterization, and biventricular and coronary angiography before surgical removal of a growth hormone-secreting pituitary adenoma. Endomyocardial biopsies were obtained and analyzed quantitatively in terms of tissue scarring and myocyte and nonmyocyte apoptosis. Myocardial samples from papillary muscles of patients who underwent valve replacement for mitral stenosis were used for comparison. The presence of apoptosis in myocytes and interstitial cells was determined by confocal microscopy with the use of 2 histochemical methods, consisting of terminal deoxynucleotidyl transferase (TdT) assay and Taq probe in situ ligation. Acromegaly was characterized by a 495-fold and 305-fold increase in apoptosis of myocytes and nonmyocytes, respectively. The magnitude of myocyte apoptosis correlated with the extent of impairment in ejection fraction and the duration of the disease. A similar correlation was found with the magnitude of collagen accumulation, indicative of previous myocyte necrosis. Myocyte death was independent from the hormonal levels of growth hormone and insulin-like growth factor-1. Apoptosis of interstitial cells did not correlate with ejection fraction.
Myocyte cell death, apoptotic and necrotic in nature, may be critical for the development of ventricular dysfunction and its progression to cardiac failure with acromegaly.
未经治疗的肢端肥大症长期发展会导致一种以心室功能障碍和衰竭为特征的非特异性肌病。然而，导致心脏泵功能改变的机制仍有待明确。由于细胞死亡与大多数心脏疾病过程相关，因此有人提出肢端肥大症患者的心肌细胞可能会发生凋亡，从而导致心室血流动力学恶化。
10例伴有舒张功能障碍的肢端肥大症患者以及4例同时伴有收缩功能障碍的患者，在手术切除分泌生长激素的垂体腺瘤之前，接受了心电图、动态心电图监测、二维超声心动图、心导管检查以及双心室和冠状动脉造影。获取心内膜活检组织，并对组织瘢痕形成、心肌细胞和非心肌细胞凋亡进行定量分析。选取因二尖瓣狭窄接受瓣膜置换术患者的乳头肌心肌样本作为对照。采用共聚焦显微镜，通过末端脱氧核苷酸转移酶（TdT）检测和Taq探针原位连接这两种组织化学方法，确定心肌细胞和间质细胞中凋亡的存在情况。肢端肥大症患者的心肌细胞凋亡增加了495倍，非心肌细胞凋亡增加了305倍。心肌细胞凋亡的程度与射血分数受损程度以及疾病持续时间相关。与胶原蛋白积累程度也存在类似的相关性，提示既往存在心肌细胞坏死。心肌细胞死亡与生长激素和胰岛素样生长因子-1的激素水平无关。间质细胞凋亡与射血分数无关。
心肌细胞死亡，包括凋亡和坏死，可能是肢端肥大症患者心室功能障碍发展及其进展为心力衰竭的关键因素。
