Circulation Research. 2003;93:604-613
Published online before print September 4, 2003, doi: 10.1161/01.RES.0000093985.76901.AF
Published online before print September 4, 2003, doi: 10.1161/01.RES.0000093985.76901.AF
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© 2003 American Heart Association, Inc.
Clinical Research |
Senescence and Death of Primitive Cells and Myocytes Lead to Premature Cardiac Aging and Heart Failure
From the Cardiovascular Research Institute (C. Chimenti, J.K., D.T., K.U., H.H., C. Colussi, F.D.M., B.N.-G., A.F., A.L., P.A.), Department of Medicine, New York Medical College, Valhalla, NY; Department of Cardiology (A.F.), Sacred Heart University, Rome, Italy; and Department of Cardiology (A.M.), San Raffaele Hospital, Milan, Italy.
Correspondence to Piero Anversa, MD, Cardiovascular Research Institute, Department of Medicine, New York Medical College, Vosburgh Pavilion, Room 302, Valhalla, NY 10595. E-mail piero_anversa{at}nymc.edu
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.
Key Words: aging • telomeric shortening and telomerase activity • p16INK4a marker of cellular senescence • cardiac primitive cells • heart failure
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