Chimenti Cristina, Kajstura Jan, Torella Daniele, Urbanek Konrad, Heleniak Hubert, Colussi Claudia, Di Meglio Franca, Nadal-Ginard Bernardo, Frustaci Andrea, Leri Annarosa, Maseri Attilio, Anversa Piero
Cardiovascular Research Institute, Department of Medicine, New York Medical College, Vosburgh Pavilion, Room 302, Valhalla, NY 10595, USA.
Circ Res. 2003 Oct 3;93(7):604-13. doi: 10.1161/01.RES.0000093985.76901.AF. Epub 2003 Sep 4.
Chronological myocardial aging is viewed as the inevitable effect of time on the functional reserve of the heart. Cardiac failure in elderly patients is commonly interpreted as an idiopathic or secondary myopathy superimposed on the old heart independently from the aging process. Thus, aged diseased hearts were studied to determine whether cell regeneration was disproportionate to the accumulation of old dying cells, leading to cardiac decompensation. Endomyocardial biopsies from 19 old patients with a dilated myopathy were compared with specimens from 7 individuals of similar age and normal ventricular function. Ten patients with idiopathic dilated cardiomyopathy were also analyzed to detect differences with aged diseased hearts. Senescent cells were identified by the expression of the cell cycle inhibitor p16INK4a and cell death by hairpin 1 and 2. Replication of primitive cells and myocytes was assessed by MCM5 labeling, myocyte mitotic index, and telomerase function. Aged diseased hearts had moderate hypertrophy and dilation, accumulation of p16INK4a positive primitive cells and myocytes, and no structural damage. Cell death markedly increased and occurred only in cells expressing p16INK4a that had significant telomeric shortening. Cell multiplication, mitotic index and telomerase increased but did not compensate for cell death or prevented telomeric shortening. Idiopathic dilated cardiomyopathy had severe hypertrophy and dilation, tissue injury, and minimal level of p16INK4a labeling. In conclusion, telomere erosion, cellular senescence, and death characterize aged diseased hearts and the development of cardiac failure in humans.
按时间顺序的心肌老化被视为时间对心脏功能储备的必然影响。老年患者的心力衰竭通常被解释为叠加在老年心脏上的特发性或继发性心肌病，与衰老过程无关。因此，对老年患病心脏进行研究，以确定细胞再生是否与衰老死亡细胞的积累不成比例，从而导致心脏失代偿。将19例患有扩张型心肌病的老年患者的心内膜活检标本与7例年龄相仿且心室功能正常的个体的标本进行比较。还分析了10例特发性扩张型心肌病患者，以检测与老年患病心脏的差异。通过细胞周期抑制剂p16INK4a的表达鉴定衰老细胞，通过发夹1和2鉴定细胞死亡。通过MCM5标记、心肌细胞有丝分裂指数和端粒酶功能评估原始细胞和心肌细胞的复制。老年患病心脏有中度肥大和扩张，p16INK4a阳性原始细胞和心肌细胞积累，且无结构损伤。细胞死亡明显增加，且仅发生在表达p16INK4a且端粒显著缩短的细胞中。细胞增殖、有丝分裂指数和端粒酶增加，但无法补偿细胞死亡或阻止端粒缩短。特发性扩张型心肌病有严重的肥大和扩张、组织损伤，且p16INK4a标记水平极低。总之，端粒侵蚀、细胞衰老和死亡是老年患病心脏和人类心力衰竭发展的特征。
