Correspondence
Evidence That Human Cardiac Myocytes Divide after Myocardial Infarction
N Engl J Med 2001; 345:1130-1131October 11, 2001
- Article
To the Editor:
Beltrami et al. (June 7 issue)1 are to be congratulated for their elegant demonstration that mitosis can occur in the human ventricle. It should be noted, however, that the ability of mammalian cardiac myocytes to divide has been described by many investigators since the end of the 19th century. Rumyantsev, in a 1977 review, stated that “a limited percentage” of adult mammalian ventricular myocytes can overcome the most rigid restraints regarding the resumption of DNA synthesis and “pass through all phases of the mitotic cycle.”2 He also noted that the capacity for mitosis is even greater in the myocytes of mammalian atria and in the myocytes of cold-blooded vertebrates.
Most of these early observations depended on the light microscope, a tool that by today's standards is rather simple; however, the carefully documented descriptions of mitosis are convincing. Ring, for example, examined tissue at the edge of experimental infarcts in cat and rabbit ventricles, where mechanical stresses that activate proliferative signaling by cell-adhesion molecules are maximal.3 Although mitotic figures were observed within the noninfarcted myocytes, regeneration was limited to the budding of a few new cells, causing only an “expansion of the muscle end, which sends out short processes into the surrounding tissue.” Ring described this as a “failure of regeneration.”
These early observations underscore Rosenthal's4 caution that even though adult cardiac myocytes are able to divide, much remains to be done before their limited potential for mitosis can be used clinically to generate a significant mass of functioning myocardium.
4 ReferencesArnold M. Katz, M.D.
University of Connecticut School of Medicine, Farmington, CT 06030
arnold.m. katz@dartmouth. edu 1
Beltrami AP ,Urbanek K ,Kajstura J , et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001;344:1750-1757
Full Text | Web of Science | Medline2
Rumyantsev PP . Interrelations of the proliferation and differentiation processes during cardiact myogenesis and regeneration. Int Rev Cytol 1977;51:187-273
CrossRef3
Ring PA . Myocardial regeneration in experimental ischaemic lesions of the heart. J Pathol Bacteriol 1950;62:21-27
CrossRef | Web of Science | Medline4
Rosenthal N . High hopes for the heart. N Engl J Med 2001;344:1785-1787
Full Text | Web of Science | Medline
To the Editor:
In identifying myocytes undergoing mitosis at the border of infarcts, is it possible that Beltrami and colleagues stumbled onto the key to sudden cardiac death and postinfarction ventricular tachycardia? The classic histopathological–electrophysiological study of postinfarction ventricular tachycardia1 and subsequent investigations that involved the use of more advanced mapping techniques established that the mechanism underlying these arrhythmias involves reentry along the border zone between infarcted cells and functioning myocytes. It would be of great interest to know the proportion of patients in the current study who had ventricular arrhythmias before death or who died because of arrhythmia. It may be possible that the myocytes generated by mitosis constitute the substrate for arrhythmias; a further hypothesis is that this process occurs as these immature cells allow disordered depolarization, without organized contraction.
1 ReferencesSubha V. Raman, M.D.
Glen E. Cooke, M.D.
Philip F. Binkley, M.D.
Ohio State University, Columbus, OH 43210
raman-1@medctr.osu. edu 1
DeBakker JMT ,van Capelle FJL ,Janse MJ , et al. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: electrophysiologic and anatomic correlation. Circulation 1988;77:589-606
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To the Editor:
In a study cited by Beltrami et al., Linzbach1 showed increased numbers of myocyte nuclei and cardiac-muscle fibers in concentrically hypertrophied human hearts larger than 500 g. In the study by Beltrami et al., the mean weight of the infarcted hearts was 497±129 g, whereas the control hearts weighed 361±51 g. Therefore, these investigators' observations could have been due partly to cardiac hypertrophy.
1 ReferencesBruce I. Goldman, M.D.
John Wurzel, M.D.
Temple Medical School, Philadelphia, PA 19140
goldmanb@astro.temple. edu 1
Linzbach AJ . Heart failure from the point of view of quantitative anatomy. Am J Cardiol 1960;5:370-382
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Author/Editor Response
The authors reply:
To the Editor: We agree with Katz that the demonstration of mitosis in adult human ventricular myocytes is not new, and in our article we cite our first documentation of myocyte cytokinesis (in 1998).1 We also agree that Rumyantsev made accurate histologic descriptions of occasional karyokinesis in rat myocytes; more recently, Rumyantsev contributed to a book2 to which we also contributed a chapter supporting the same concept. However, this work and our other publications over the past 12 years have been challenged or dismissed.3 The myocardium continues to be considered a terminally differentiated tissue, with its response to injury or overloads restricted to myocyte hypertrophy, in the absence of regeneration; at best, myocyte division is regarded as a curiosity without physiologic implications. It appears that our work has done nothing to change the old paradigm that in the adult heart, myocyte hypertrophy is the only relevant form of cardiac growth. Katz fails to acknowledge that our findings — a high number of cells in mitosis and cycling myocytes in the infarct border zone and, most important, in the distant, well-perfused, viable myocardium — challenge the conventional dogma.
Documentation of myocyte proliferation requires the demonstration of an absolute increase in cell number.4 We have shown increases in the number of myocytes in excess of 40 to 50 percent in animals and humans, despite apoptosis and necrosis.5 This work strongly suggests that cardiac growth in the adult heart is not limited to cellular hypertrophy. Myocyte proliferation is equally important in homeostasis and remodeling and cannot be ignored any longer. This is now clear with respect to the adult brain, which was also believed to contain only terminally differentiated, irreplaceable parenchymal cells. This concept has been defeated, and we expect that it will be defeated with respect to the heart as well.
Without the relevant data, we cannot rule out myocyte proliferation as a factor contributing to arrhythmia, as suggested by Raman et al. However, it seems unlikely that dividing myocytes trigger reentry mechanisms. Finally, lack of correlation between the weight of the heart and myocyte replication makes it unlikely that myocyte proliferation is due to hypertrophy, as suggested by Goldman and Wurzel. Nevertheless, cardiac hypertrophy does involve myocyte hyperplasia.
5 ReferencesPiero Anversa, M.D.
Bernardo Nadal-Ginard, M.D., Ph.D.
New York Medical College, Valhalla, NY 10595
piero_anversa@nymc.edu 1
Kajstura J ,Leri A ,Finato N ,Di Loreto C ,Beltrami CA ,Anversa P . Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A 1998;95:8801-8805
CrossRef | Web of Science | Medline2
Rumyantsev PP. Replicative behavior of different types of cardiomyocytes in terms of experimental conditions, age and systematic position of animals. In: Oberpriller JO, Oberpriller JC, Mauro A, eds. The development and regenerative potential of cardiac muscle. London: Harwood Academic, 1991:53-80.
3
Soonpaa MH ,Field LJ . Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res 1998;83:15-26
Web of Science | Medline4
Baserga R. The biology of cell reproduction. Cambridge, Mass.: Harvard University Press, 1985.
5
Anversa P ,Kajstura J . Ventricular myocytes are not terminally differentiated in the adult mammalian heart. Circ Res 1998;83:1-14
Web of Science | Medline
