Endomitosis and polyploidization of myocardial cells in the periphery of human acute myocardial infarction.
OBJECTIVE
Although the genetic program for reinitiating DNA synthesis exists in post-mitotic cardiomyocytes, and it was reported that in human acute myocardial infarction (AMI) a significant proportion of myocytes enter mitosis, the rule is that the lost tissue is replaced by a collagen scar. The purpose of this study was to search for the basis of this discordance in order to devise future strategies to induce division of myocytes into daughter cells that may replace the lost tissue with contractile cells.


METHODS
In 15 human hearts with 1- to 21-day-old infarcts, the expression of the cell cycle proteins Ki67 antigen, cyclins D, A, and B1, the presence of mitotic bodies, and the ploidy status were investigated with immunoenzymatic methods, light and laser confocal microscopy, and densitometry in the myocytes surrounding the infarct area.


RESULTS
In 7- to 13-day-old infarcts, 11.61+/-6.94% of the myocytes presented Ki67+ nuclei, and a lower proportion presented cyclins D, A, and B. At earlier and later times, the proportion of Ki67+ myocytes was significantly lower. Although under confocal microscopy and fluorescent labels, some of the Ki67+ myocytes appeared to be in different stages of mitosis, with Nomarski optics and hematoxylin counterstaining, the condensed chromosomes, although arranged in metaphase and anaphase plates or split in sister chromatids, were always located within a preserved nuclear envelope, indicating the presence of endomitosis. Conventional mitosis was exceptionally observed. In the 14- and 21-day-old infarcts, the ploidy of the myocytes adjacent to the infarct was significantly higher than in distant zones.


CONCLUSIONS
These observations indicate that in human infarcts, entrance of cardiomyocytes into the cell cycle is transient and that endomitosis, leading to polyploidy, rather than mitosis, leading to karyokinesis, is the final fate of cycling cells. Both observations may account for the discordance between the regenerative ability of myocytes and the lack of an efficient reparative process in human AMI.
Meckert
Patricia Cabeza
PC
Division of Pathology, Institute of Cardiology and Cardiovascular Surgery, Favaloro Foundation, Buenos Aires, Argentina.
Rivello
Hernán García
HG
Vigliano
Carlos
C
González
Pedro
P
Favaloro
Roberto
R
Laguens
Rubén
R
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000032:analysis*; D019925:Cyclin A / Q000032:analysis; D019926:Cyclin B / Q000032:analysis; D056744:Cyclin B1; D056741:Cyclin D; D016213:Cyclins / Q000032:analysis; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D008938:Mitosis; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000737:chemistry* / Q000473:pathology; D011123:Polyploidy
D015415:Biomarkers; C534699:CCNB1 protein, human; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019926:Cyclin B; D056744:Cyclin B1; D056741:Cyclin D; D016213:Cyclins; D019394:Ki-67 Antigen