Myocyte proliferation in end-stage cardiac failure in humans

Abstract

Introduced several decades ago, the dogma persists that cardiac myocytes are terminally differentiated cells and that division of muscle cells is impossible in the adult heart. More recently, nuclear mitotic divisions in myocytes occasionally were seen, but those observations were challenged on the assumption that the rate of cell proliferation was inconsequential for actual tissue regeneration. Moreover, mitoses were never detected in normal myocardium. However, the analysis of routine histologic preparations constituted the basis for the belief that myocytes were unable to reenter the cell cycle and divide, ignoring the limitations of these techniques. We report here by confocal microscopy that 14 myocytes per million were in mitosis in control human hearts. A nearly 10-fold increase in this parameter was measured in end-stage ischemic heart disease (152 myocytes per million) and in idiopathic dilated cardiomyopathy (131 myocytes per million). Because the left ventricle contains 5.8 ؋ 10 9 myocytes, these mitotic indices imply that 81.2 ؋ 10 3 , 882 ؋ 10 3 , and 760 ؋ 10 3 myocytes were in mitosis in the entire ventricular myocardium of control hearts and hearts affected by ischemic and idiopathic dilated cardiomyopathy, respectively. Additionally, mitosis lasts less than 1 hr, suggesting that large numbers of myocytes can be formed in the nonpathologic and pathologic heart with time. Evidence of cytokinesis in myocytes was obtained, providing unequivocal proof of myocyte proliferation.

Myocardial Morphological Characteristics and Proarrhythmic Substrate in the Rat Model of Heart Failure Due to Chronic Volume Overload

“…This is in contrast with asymmetric cellular hypertrophy in pressure overload model (Campbell et al, 1989), where most pronounced hypertrophy was found in the subendocardial layers. The interesting discrepancy between continued increase in ventricular wall thickness that could not be explained by increased myocyte dimensions, especially in the right ventricle (Table 2) suggests, in the notable absence of fibrosis, that there could be activation of myocyte (or resident stem cells) proliferation, that was recognized previously in decompensated HF in humans (Kajstura et al, 1998).…”

Stem cells in the heart: What's the buzz all about?—Part 1: Preclinical considerations

“…A myocyte mitotic index of 0.0014% in control hearts and 0.013% to 0.015% in diseased hearts was determined by confocal analysis. 2 Those initial data were confirmed and amplified in an autopsy study of human hearts 3 in which actively dividing cardiomyocytes (evidenced by Ki67 expression, a nuclear antigen expressed in dividing cells 4 ) resulted in mitotic indices of 0.08% and 0.03% in the regions adjacent to and distant from the infarcts, respectively. In principle, mitotic figures in the heart could arise from preformed cardiomyocytes released from cell cycle inhibition or from resident cardiomyocyte precursors or stem cells that become activated.…”

Entrance in mitosis of adult cardiomyocytes in ischemic pig hearts after plasmid-mediated rhVEGF165 gene transfer

“…Mitotic CMN index was calculated according to previously described procedures for dog 16 and human 13,17 hearts. The numerical density of CMN per unit area of myocardium was obtained in each heart by counting in a 5 mm 2 area of the lateral wall mesocardium the number of CMN in longitudinally oriented cells containing sarcomeric a-actin.…”