© 1998 American Heart Association, Inc.
Point/Counterpoint |
Ventricular Myocytes Are Not Terminally Differentiated in the Adult Mammalian Heart
From the Department of Medicine, New York Medical College, Valhalla.
Key Words: cell proliferation • cell death • insulin-like growth factor-1 • cell cycle
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Terminally Differentiated Cells |
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 Top Terminally Differentiated Cells History of the Terminally...Postnatal Myocardial GrowthAging of the MyocardiumHeart FailureIGF-1 and Myocyte GrowthReferences |
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Primary cultures of various cell types contain dividing and nondividing cells.1 2 However, nondividing cells can rest in the G0 phase and reenter the cell cycle on stimulation3 4 5 or become terminally differentiated and die without dividing.6 This third category of cells is not dormant in G0 and cannot reenter the cell cycle.6 For example, such a phenomenon is present in vivo at the tip of the villi of the small intestine,7 in the auditory hair cells of the ear,8 and in the upper layers of the epidermis.9 In contrast, hepatocytes in vivo are in a G0 state,10 11 12 and after partial hepatectomy or severe injury, liver regeneration is accomplished by proliferation of mature hepatocytes as well as biliary epithelial cells and fenestrated endothelial cells.12 The reconstitution of liver mass is not dependent on a reserve of stem cells, which condition regeneration of bone marrow13 and skin.14 Multipotential cells have also been identified in the central nervous system, but their ability to grow, differentiate, and ultimately survive has been problematic.15 In skeletal muscle, satellite cells can be stimulated to proliferate and develop into mature myocytes, representing an additional form of tissue regeneration.16 17 18 These mechanisms of cellular growth have not been considered possible in adult cardiac myocytes, and the concept was advanced that no proliferation of ventricular muscle cells occurs once cell division has ceased, shortly after birth in the mammalian heart.19
The dogma was introduced that adult cardiac myocytes are terminally differentiated cells and, therefore, cannot be recalled into the cell cycle.20 21 These cells are not in G0, cannot be triggered into the proliferative phase, but can perform their physiological functions, undergo cellular hypertrophy, and ultimately die. On this basis, in vitro preparations of neonatal cardiac myocytes22 23 24 and skeletal muscle cell lines25 have been used for the analysis of the molecular control of the cell cycle in an attempt to identify the key factors of terminal differentiation of myocytes. However, we will challenge the premise that myocytes cannot reenter the cell cycle, synthesize DNA, undergo nuclear mitotic division, and proliferate in vivo in the adult heart. To the best of our knowledge, there is not a single piece of evidence that this cell population is terminally differentiated in vivo. Such a contention requires the demonstration that after mitosis these cells have entered a physiological state from which they cannot be rescued by an appropriate stimulus and that they are not able to leave this condition of terminal differentiation, duplicate DNA, and increase in number, regardless of the disease process and the magnitude of myocardial mass. It is rather surprising that in vivo documentation of the replicative capacity of fully differentiated ventricular myocytes21 is questioned in view of the absence of mitosis in artificial in vitro preparations mostly restricted to neonatal myocytes.22 23 24 The logical expectation would be the opposite. This article will review available information obtained in vivo in animal models and humans favoring and opposing the belief that myocyte cellular hyperplasia is a significant component of the growth mechanisms of the overloaded heart.
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History of the Terminally Differentiated Myocyte |
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TopTerminally Differentiated CellsHistory of the Terminally...Postnatal Myocardial GrowthAging of the MyocardiumHeart FailureIGF-1 and Myocyte GrowthReferences |
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Numerous studies of the human heart from 1850 to 1911 held the view that myocardial hypertrophy was the consequence of hyperplasia and hypertrophy of existing myocytes.26 27 28 29 30 31 32 33 34 35 However, subsequent reports from 1921 to 1925 have questioned the ability of myocytes to proliferate, suggesting that the increase in cardiac muscle mass in the pathological heart was the result of pure cellular hypertrophy.36 37 38 The concept that myocytes cannot divide originated from the difficulty of identifying mitotic figures in the cells and not from any estimation of myocyte cell volume and number.38 Such a conviction has gained support from the autoradiographic analysis of [3H]thymidine incorporation in hearts of animals during postnatal development39 and after conditions of overload.40 41 42 DNA synthesis in myocyte nuclei either was not detected or was found to be essentially negligible. Although we will subsequently provide evidence to the contrary, the lack of DNA replication in cardiac myocytes experimentally with physiological growth and cardiac hypertrophy and the inability to recognize mitoses in the enlarged human heart led to the conclusion that this cell population is not in a G0 state, cannot reenter the cell cycle, and is, therefore, terminally differentiated.
There are 4 issues that must be emphasized: (1) Results in animals of different species are not directly applicable to the human heart. (2) Postnatal myocardial growth is a slow physiological process that involves several maturational changes in myocytes, including differentiation and multinucleation; myocardial hypertrophy in the adult is accomplished by the growth response of mature myocytes, which is influenced by the nature and degree of the overload. (3) [3H]Thymidine labeling cannot be equated with an increase in cell number. (4) The presence or absence of cell proliferation can be determined only by counting the number of cells. We will first summarize observations concerning the changes in number and size of ventricular myocytes from birth to adulthood in humans and animals and subsequently relate how aging and pathological loads affect these cellular characteristics. Finally, evidence supporting the role of insulin-like growth factor-1 (IGF-1) in stimulating adult ventricular myocytes to reenter the cell cycle and ultimately divide will be discussed.
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Postnatal Myocardial Growth |
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TopTerminally Differentiated CellsHistory of the Terminally...Postnatal Myocardial GrowthAging of the MyocardiumHeart FailureIGF-1 and Myocyte GrowthReferences |
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The expansion of cardiac mass postnatally is accomplished by increases in myocyte size and number.19 43 However, the cellular changes taking place in the human heart have not been carefully defined. There is no information on myocyte volume at birth in the 2 ventricles, although the claim has been made that myocyte diameter is comparable shortly after birth in the left and right sides of the heart44 45 but that later in life left ventricular myocytes are slightly larger than right ventricular myocytes.46 47 The total number of ventricular myocytes at birth is
1x109,48 49 but this
parameter is extremely
variable.50 51 Recently, myocyte number has
been measured in the male and female human heart at 20 years of age.
The male left ventricle contains 5.8x109
myocytes, and the right ventricular free wall possesses
2.0x109 muscle cells.46 47
Corresponding values in the female heart are
4.5x109 and 1.4x109
myocytes.47 These data suggest that a significant
increase in myocyte number occurs in both ventricles with maturation in
men and women. However, whether the process of cell proliferation
persists in this 20-year period or is completed by 5 months after
birth51 52 or earlier53
remains to be determined. The lack of knowledge involving the cellular
mechanisms implicated in the growth of the heart during
physiological cardiac hypertrophy is
part of the uncertainty concerning whether ventricular
myocytes in humans actually become terminally differentiated rapidly
after birth. Cells are believed to be retained throughout adult life
and not to be replaced if they die. Understanding why such a condition
should exist in the heart is rather complex, since myocytes are
continuously lost as a function of aging
alone43 46 47 54 and in combination with various
pathological states.54 55 56 57 58 Myocyte volume
markedly increases postnatally,52 59 but further
hypertrophy is limited in
adulthood.60 As stated in Molecular Biology
of the Cell,61 "... it is difficult to
give any reason at all" why heart muscle cells should be permanent
and irreplaceable.
Similar problems exist in understanding the role of myocyte
hypertrophy and hyperplasia in the developing heart of the
rat, the animal model most extensively
investigated.43 62 63 64 65 66 67 More limited studies have
also been performed in mice.39 68 69 Two
essential processes occur in the prenatal period: myocyte mitotic
division and structural differentiation of the myocyte cytoplasm,
involving the synthesis and organization of myofibrils and other
cytoplasmic components.19 70 71 72 In an attempt to
evaluate the contribution of myocyte proliferation prenatally and
postnatally, the extent of DNA synthesis in myocytes has recently been
measured in rats73 and
mice.69 However, the behavior of the rat heart
differs from that of the mouse heart. Bromodeoxyuridine (BrdU) labeling
of left ventricular myocytes involves nearly 17% of cells
in the fetal rat heart at the end of gestation, decreasing to 13% one
day after birth. In the adult rat heart, values of
0.2%,73 0.45%,74
0.9%,75 and 2%76 have
been reported. Conversely, in the mouse, DNA synthesis is markedly
reduced at birth but increases to 10% at neonatal days 4 and 5. DNA
replication disappears at day 10 and remains absent later in
life.69 However, Petersen and
Baserga39 demonstrated in 1965 that DNA synthesis
occurs in myocyte nuclei of the mouse heart, and a thymidine labeling
index of 2.2% was found at 32 days of age. Lower percentages of
myocyte nuclei labeling and earlier disappearance of DNA replication
also have been described.77 78 The inability of
myocytes to synthesize DNA may not apply to all strains of mice; a
mitotic image in a myocyte of the left ventricle of a normal FVB/N
mouse at 2.5 months of age is illustrated by confocal microscopy in
Figure 1
. Mitosis in myocytes has been
detected in rats at 2 months of age as well.79
Although differences exist in the literature, the apparent contrasting
observations in rats and mice have suggested opposite conclusions:
myocytes maintain low levels of DNA replication in the normal adult rat
heart,73 74 75 76 whereas this capacity is excluded in
the adult mouse myocardium. In the latter case, it is
proposed that myocyte proliferation is completed prenatally, and
postnatal DNA synthesis reflects binucleation
only.69
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A few comments have to be made in an attempt to explain the discrepancy in magnitude and timing of DNA labeling between the rat and mouse heart. In different species, including humans, the mammalian heart varies dramatically in weight, although myocyte cell volume remains relatively constant.46 47 68 80 81 Similarly, in individual species, the greater muscle mass of the left ventricle with respect to the right ventricle is only minimally influenced by myocyte size.46 47 53 80 Myocyte cell number is the critical factor responsible for the increases in cardiac weight in larger animals. On this basis, it is reasonable to assume that heavier hearts with several-fold higher numbers of myocytes may undergo DNA replication and myocyte proliferation for longer periods of time after birth. The persistence of thymidine labeling in myocyte nuclei postnatally in the rat heart has been observed in several other studies,82 83 84 85 86 indicating that mice and rats may not be identical in this cellular aspect. Moreover, caution should be exercised in the interpretation of BrdU and thymidine labeling data as indicators of the terminal differentiation of myocytes. An example is given below.
Recently, the suggestion has been made that DNA replication in myocytes at day 4 and later in rats is coupled with binucleation exclusively, in the absence of cell proliferation.87 This conclusion was reached since a single injection of BrdU at day 4, when most of the cells are mononucleated, resulted in the same percentage of positively labeled myocytes at 2 hours and up to 8 days after BrdU administration. Myocyte binucleation has been claimed to be completed by day 12.87 However, the BrdU labeling index in the manner used has little to do with either binucleation or lack of cell division. Let us assume that 10 myocytes are present in the heart and that 2 mononucleated cells incorporate BrdU, ie, 20%. If these 2 myocytes become binucleated as do the remaining 8 cells, 2 myocytes (4 nuclei) out of 10 (20 nuclei) will be labeled, ie, 20% of the population. Consistent with the authors' contention, BrdU staining was associated with binucleation without cell proliferation. Let us now consider that these 10 binucleated myocytes in which 2 are labeled by BrdU all divide, generating 20 cells (40 nuclei). As a consequence, 4 myocytes (8 nuclei) will be labeled, ie, 20%; this condition reflects a 2-fold increase in cell number in spite of an identical percentage of BrdU labeling. Let us now take into account a more complex situation: a population of 20 cells, 10 mononucleated and 10 binucleated in which 2 in each group are BrdU-labeled. If 50% of each cell category enter the cell cycle and mononucleated cells become binucleated and binucleated cells form new binucleated myocytes, the results are as follows: 5 mononucleated myocytes with 1 stained by BrdU and 20 binucleated myocytes with 4 stained by BrdU. Again, 5 BrdU-labeled cells out of 25 equals 20% of labeling in the presence of a 25% myocyte proliferation. It is relevant to emphasize that these calculations correctly consider that BrdU-labeled myocytes behave in a manner identical to unstained cells. Importantly, the claim has been made that the consistency in the fraction of myocytes labeled by BrdU over time is a demonstration of the lack of cell division, whereas an increase in labeling index would be indicative of cell multiplication.87 The latter implies that BrdU, per se, can trigger a cell to reenter the cell cycle and undergo cytokinesis. As stated in Baserga's book in 1985,6 "cell proliferation means that cells are dividing, and the only way to determine the number of cells ... is to count them." Additionally, DNA synthesis in myocyte nuclei in the rat heart does not end at day 12, when binucleation is completed. Results from our laboratory in the same strain of Sprague-Dawley rats have shown a 0.52% labeling index at 3 weeks,73 and values of 1.5% and 0.58% have been reported from Clubb and Bishop67 for the left and right ventricles of Fischer 344 rats at the identical age.
Quantitative analyses of the changes in myocyte number in the heart of Wistar and Sprague-Dawley rats with maturation are rare; the results are variable; and the differences are, at times, difficult to explain.86 87 88 89 90 91 92 However, the major increases in cell number appear to occur in the early postnatal period, a phenomenon that may also apply to the mouse heart.68 93 The contradictory observations may reflect, at least in part, the limitations inherent in the methodologies used and instrumentation available at the time of these investigations. Additionally, not a single experiment examined the changes in myocyte cell volume and number at different time points during postnatal development and in the adult heart simultaneously. The number of myocytes in the right ventricle achieves an adult value almost immediately after birth,88 and numerous studies have examined the entire heart, neglecting the possibility of regional differences in myocyte proliferation. The deficiencies in the in situ morphometric techniques involve several factors: (1) The presence of multinucleated myocytes could not be detected in histological sections, affecting the recognition of the various cell populations in situ.94 (2) Neither the percentage of myocardium occupied by mononucleated and multinucleated myocytes nor the relative contribution of each cell category to the aggregate myocyte mass could be determined.81 (3) In situ determinations of cell volume were restricted to myocyte volume per nucleus, and cell number was based on the measurement of the total number of nuclei in the ventricle.94 (4) The enzymatic dissociation of myocytes, which allows evaluation of the percentages of mononucleated and multinucleated cells,64 was not used in early studies.88
Problems also exist in the assessment of myocyte volume of isolated cells by Coulter counter from which cell number was calculated: (1) A cell suspension is run through the machine, and the distribution curve generated by the computer requires that an arbitrary gate be introduced by the observer to establish what will be considered a reliable value of cell volume. This approach results in the exclusion of small and large myocytes, introducing a bias factor, defeating the principle of morphometry. (2) Fragments of myocytes, comparable in volume to an assumed acceptable cell size, are included in the estimation of this parameter. Aggregates of interstitial cells are commonly present at this stage, further weakening the validity of this technique. (3) Coulter counter data do not provide information regarding the volume of mononucleated and multinucleated cells, which is critical for assessment of the total number of myocytes in the ventricles.
In summary, whether an increase in cell number occurs in the myocardium in the later phases of postnatal development remains to be determined. Future studies applying morphometric methodologies in situ in combination with myocyte isolation and confocal microscopy68 81 95 will enable us to establish whether cell division is a critical aspect of the maturation of the heart. However, the question whether myocytes become terminally differentiated shortly after birth, ie, cannot reenter the cell cycle, may be negatively answered. DNA synthesis and nuclear mitotic division persist in the adult mammalian heart. The apparent discrepancies between the ability of myocytes to divide and the quantitative results may reflect ongoing cell dropout with aging and the possibility of a slow continuing turnover of old dying myocytes and new cells.
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Aging of the Myocardium |
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TopTerminally Differentiated CellsHistory of the Terminally...Postnatal Myocardial GrowthAging of the MyocardiumHeart FailureIGF-1 and Myocyte GrowthReferences |
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According to the dogma, the number of muscle cells in the mammalian heart is defined at birth, and in the absence of cardiac disease, these myocytes persist throughout the life of an individual or animal. Men and women of 100 years of age and older are present in our society, and nobody dies without a heart. The inevitable implication of the dogma is that myocytes are immortal. Alternatively, myocytes may not live indefinitely, they may have a predetermined life span, and the heart may be characterized by ongoing cell loss and cell regeneration during the entire life of a human being or an animal. We will summarize available information supporting the concept that myocyte death occurs with aging; more complex is recognizing whether cell renewal accompanies the progression of life in the normal heart.
In the last 25 years, numerous investigations have been performed to identify the pathophysiological bases responsible for the diminished ability of the aged heart to sustain increases in pressure and volume loads.58 96 97 98 99 100 Moreover, the adaptation of the coronary vasculature and microvasculature with aging has been characterized functionally and structurally.43 54 96 101 102 103 Effort has also been made to identify the molecular mechanisms implicated in the limitations of the aged heart to adapt to stressful conditions.104 105 However, to the best of our knowledge, there are only 2 studies in which the alterations in the number of ventricular myocytes with aging alone have been measured in the male46 47 and female47 human heart. In the male heart, from 17 to 89 years of age, the absolute number of myocytes decreases by 45 million per year in the left ventricle and by 19 million per year in the right ventricle. In contrast, the number of myocytes in the left and right ventricles remains essentially constant in women from 20 to 95 years of age. Myocyte loss in the male heart is associated with hypertrophy of the remaining cells. Cell volume is not altered in women. Importantly, the etiology of myocyte death in the aging human heart remains to be determined.
The bases for the differential effects of aging on ventricular myocytes in men and women are currently unknown. Although cardiovascular events in women increase after menopause,100 106 sex hormones do not appear to influence myocyte loss with aging. The number of myocytes in the myocardium does not decrease in women from 55 to 95 years.47 It is surprising that no information is available concerning the influence of gender on the volume composition of the myocardium and quantitative structural properties of the capillary network controlling tissue oxygenation as a function of aging. However, apoptosis of myocytes occurs in both men and women under pathological conditions,107 108 109 110 suggesting that the female heart is not protected from this form of cell death. Similarly, cell necrosis is present in women with ischemic cardiomyopathy.111 112 It is unlikely that cell death is not a component of the aging female heart. Conversely, the hypothesis may be advanced that the regenerative capacity of myocytes is greater in women, maintaining the number of myocytes constant. Additionally, when normal aging is not distinguished from the superimposition of hypertension, valvular disorders, diabetes, amyloidosis, and ischemic heart disease, which all increase in the elderly,113 no difference is detected between the sexes, and cardiac weights increase up to 110 years of age.114 The inclusion of myocardial hypertrophy of various origin in the study of the aging heart has indicated that the number of myocytes does not change in the left and right ventricles up to 90 years.51 115 These apparent contradictory observations are difficult to explain. However, the suggestion can be made that myocyte proliferation may occur in the hypertrophied ventricles,116 masking the phenomenon of cell loss.
In view of the difficulty in identifying the mechanisms of myocyte loss
and the potential of cell proliferation in the human heart with age,
these cellular processes have been studied in aging male Fischer 344
rats. In this strain and sex, cell death has been detected as early as
3 months after birth in the left and right ventricles. However, myocyte
necrosis and apoptosis are both present in the left
ventricle, whereas myocyte necrosis exclusively affects the right
ventricle.117 This distinction in the forms of
cell death between the ventricles persists throughout life. Myocyte
death increases with age, but a reduction in the total number of
myocytes of nearly 19% occurs biventricularly only at 12
months.118 Myocyte number in the left ventricle
does not change from 12 to 29 months, and a 1.8-fold increase takes
place in the right ventricle during this interval. The preservation of
the aggregate number of muscle cells in the left and the increase in
the right ventricle with age occur in spite of the concurrent loss of
myocytes in the entire heart.117 Myocyte death
and regeneration are easily identified in adult rats at 3 to 4 months,
since not only are apoptosis and necrosis present, but BrdU
labeling and nuclear mitotic division are also observed in these cells
(Figure 2). Ventricular
dysfunction and failure in this model become apparent at 24 to 29
months,97 98 117 118 minimizing the role of
hemodynamic factors in cell death and proliferation in
young animals. Thus, adult myocytes are not immortal and may have a
predetermined life span, and new cells can be made by mitotic division.
However, whether old cells are more predisposed to die cannot be
established at present. There are no markers of myocyte aging, and
the acquisition of tools capable of discriminating senescent from young
cells99 119 may be a major challenge of future
research.
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The combination of cell death, DNA replication, and myocyte nuclear mitotic division is not restricted to Fischer 344 rats. BrdU labeling of myocyte nuclei73 74 75 and mitotic images are characteristic aspects of male Sprague-Dawley rats as well.79 Mitoses in adult myocytes79 and cell loss80 have been reported in this strain, suggesting that a balance between cell growth and cell death may be present in adult animals. In this model, as in the Fischer rat, myocyte cell loss precedes the occurrence of ventricular dysfunction.80 These experimental findings and the results in humans are consistent with the contention that myocyte cell death is a typical feature of the detrimental effect of aging on the male mammalian heart. Additionally, a slow rate of myocyte turnover may be implemented in the rat heart, but no information is available to indicate that a similar phenomenon occurs in humans. Whether sex differences are important variables that influence the susceptibility of myocytes to die and regenerate in adulthood and aging is currently unknown.
Although heart failure is a disease of the elderly, with 3.2 million
patients older than 65 years of age,120 the
results discussed above46 47 do not support the
concept that aging, per se, leads to an impairment in pump
performance. In the population examined, stringent criteria for
inclusion were followed, excluding all hearts with any form of
functional or histologically detectable myocardial
damage.46 47 However, whether heart failure in an
aged individual is always attributable to a secondary disease of the
myocardium and coronary vasculature or whether, at
times, aging may be regarded as the primary cause of the abnormality in
cardiac hemodynamics remains to be determined
clinically. This is a relevant issue, since heart failure is the major
cause of death in the elderly.58 Moreover, severe
ventricular dysfunction develops in Fischer 344 rats late
in life97,98,117,118; this deleterious impact of
aging in the animal model is characterized by a high level of mitosis
and myocyte proliferation.80 121 Flow cytometric
analyses of DNA content in myocyte nuclei have been
consistent with these results.122
Preliminary observations by confocal microscopy of BrdU-labeled myocyte
nuclei in the tissue and mitoses in isolated myocyte preparations
confirm active DNA replication (Figure 3)
and nuclear mitotic division (Figure 4)
in aged animals. Conversely, it is not clear whether these findings in
male Fischer 344 rats are actually applicable to the aged, senescent,
failing human heart.
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Heart Failure |
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TopTerminally Differentiated CellsHistory of the Terminally...Postnatal Myocardial GrowthAging of the MyocardiumHeart FailureIGF-1 and Myocyte GrowthReferences |
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The possibility that cardiac hypertrophy in humans is the result of myocyte hypertrophy and hyperplasia was advanced >40 years ago by Linzbach.45 60 The critical heart weight theory introduced by this author in the late 1940s and early 1950s has suggested that, in the presence of a cardiac weight of
500 g, myocyte proliferation begins and that this cellular
process constitutes the prevailing mechanism of additional growth of
the heart.116 These findings were restricted to
the left ventricle, but subsequent observations have demonstrated that
a similar response occurs in the right
ventricle.123 The existence of myocyte
proliferation in the human heart was challenged in
1972,51 115 but several more recent studies have
confirmed Linzbach's results.50 124 125 126 127 128 129 130
However, the morphometric data supporting cellular hyperplasia have
been based mostly on the assumption that myocytes are mononucleated
cells and that an increase in the total number of myocyte nuclei in the
ventricle corresponds to an identical increase in the aggregate number
of cells in the heart. Different proportions of mononucleated and
multinucleated myocytes may be present in the
myocardium during normal and pathological states, and this
raises the question of the distinction between nuclear hyperplasia
without cytokinesis, ie, increased number of nuclei per cell,
and cellular hyperplasia, ie, increased number of myocytes. This
critical issue has recently been addressed by examining the
distribution of nuclei in myocytes isolated from 72 normal and 176
pathological hearts.130 Aging, cardiac
hypertrophy, and ischemic
cardiomyopathy do not change the fraction of
mononucleated and multinucleated myocytes in the
ventricular myocardium.
The documentation that conditions of overload, aging, and
ischemic heart disease do not alter the relative proportion of
the various myocyte populations130 strongly
suggests that the demonstrations of myocyte cellular hyperplasia
obtained initially by Linzbach45 60 and
subsequently by other investigators50 124 125 126 127 128 129 130
are valid. Additionally, mononucleated cells represent 3/4 of
the myocytes of the human heart, differing significantly from other
mammals, such as mice,68
rats,64 and dogs.81 Whether
this cellular characteristic may influence the ability of myocytes to
reenter the cell cycle and ultimately divide is currently unknown.
Similarly, it is not clear whether the massive cardiac
hypertrophy that can be achieved in the human
heart116 125 130 is related, at least in part, to
the high percentage of mononucleated myocytes. Heart weight in humans
may increase 3-fold, reaching values of 1000
g.60 116 125 130 Decompensated eccentric
hypertrophy in humans is characterized by increases in
myocyte number that vary from 20% to
>100%.60 116 123 124 125 126 127 128 129 130 This phenomenon does not
seem to be affected by aging,129 although
difficulties exist in establishing whether myocyte proliferation in the
aged pathological heart occurred at a younger age. In an
analysis of 7112 human hearts from birth to 110 years of age,
Linzbach114 has shown that extreme forms of
cardiac hypertrophy are detectable up to the ninth decade
of life, and heart weights of 500 and 600 g are present in
patients at 100 years and older.
The morphometric results in the human heart have been questioned repeatedly, and the ability of adult myocytes to undergo hyperplasia has been a matter of controversy for several decades and still persists in the scientific community. The bases for the opposition to these quantitative findings are difficult to understand because the issue of the existence or absence of an increase in the number of myocytes in the hypertrophied decompensated human heart can be addressed only by morphometric methodologies. There is no alternative technique that can be used. Moreover, scar formation and myocyte loss are typical aspects of cardiac failure, suggesting that the measurements of myocytes in the pathological heart are underestimations of the actual number of cells that has been formed in the course of the disease. Cell death by apoptosis is present in the terminal phases of heart failure,108 110 and this ongoing process, distinct from myocyte necrosis and tissue fibrosis,131 further affects the aggregate number of cells in the ventricle. This may not be the case when cardiac hypertrophy is in its compensated stage.132
We will now consider the determinant factor on which the dogma that
ventricular myocytes are terminally differentiated cells
was based in 1925.38 As indicated earlier, this
consisted of the inability to detect mitotic figures in myocytes of
hypertrophied hearts. However, in the last few years, such
documentation has been obtained in patients affected by acute and
chronic intractable cardiac failure,21 133 and a
new example is illustrated in Figure 5.
For the first time, a mitotic index has been
measured.133 The demonstration that 11 myocyte
nuclei per 1 million cells, or 59 000 nuclei in the entire left
ventricle, exhibit mitotic images in the failing heart may explain why
difficulties exist in identifying mitoses with routine microscopic
sampling. Moreover, in most cell systems, the 4 phases of mitosis are
completed in 1 hour.6 Since there is no logical
reason to assume that the duration of mitosis is different in myocytes,
the chances of its detection in this cell population are extremely
limited. The impossibility of seeing prophase in tissue sections may
reduce further our time of recognition of mitosis. However, the low
frequency of mitosis should not suggest that this cellular process is
of minor importance in the generation of new muscle cells: in a
45-year-old man with 5.2x109 nuclei in the left
ventricle,47 a mitotic index of 11 nuclei per
106 and a mitotic time of 1 hour will generate
10% new myocytes in 1 year and almost double, 1.96-fold, the entire
number of ventricular myocytes over a period of 10 years.
These calculations assume that myocytes divide only once and are
consistent with quantitative results in the severely
hypertrophied human heart.60 116 124 125
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Experimentally, results concerning the terminal and nonterminal differentiation of ventricular myocytes in the adult heart have been contradictory. Initial observations in the late 1960s and early 1970s challenged not only the existence of myocyte proliferation but also the sequence of events postulated by Linzbach45 60 116 in which myocyte hyperplasia was regarded as a late response of the myocardium preceded by cellular hypertrophy. This is because short-term cardiac hypertrophy in the rat is characterized by enlargement of preexisting myocytes with little or no DNA synthesis in myocyte nuclei, possibly representing polyploid cells.40 41 42 However, these studies neglected the role of time and the condition of the overload. It is rather surprising that no functional measurements were obtained in these and more recent investigations to establish whether ventricular dysfunction and failure were present in the animal models. In the absence of these criteria, comparisons with the decompensated human heart are impossible.
The magnitude of the hemodynamic stress may be
the most critical variable in the initiation of myocyte
hypertrophy or hyperplasia in the pathological heart. After
a gradual and moderate increase in workload on the heart, myocyte
cellular hypertrophy
predominates,41 42 65 134 135 136 whereas a severe
increase in ventricular loading, acute and chronic in
nature, may engender DNA synthesis, mitosis, and myocyte
proliferation.83 86 137 138 139 DNA replication and
mitotic divisions in myocytes are apparent in the decompensated
postinfarcted rat heart (Figure 6).
Moreover, quantitative analysis in
rats86 118 and dogs81 139
has documented that the number of nuclei per cell does not change in
the failing heart, indicating that increases in the number of myocyte
nuclei in the ventricle correspond to identical increases in myocyte
number. Similarly, nuclear mitotic divisions reflect the generation of
new myocytes. These conclusions are in contrast with observations in
the mouse heart, in which isoproterenol-induced cardiac
hypertrophy did not show DNA replication in myocyte
nuclei.140 This apparent discrepancy may be due
to the preservation of function in this model. Conversely, BrdU
labeling of myocyte nuclei is present in the surviving
myocardium after infarction and ventricular
failure in the mouse (not shown). In this regard, cyclin
D1 overexpression in myocytes in vivo is coupled
with DNA synthesis and multinucleation.141
Whether these transgenic mice are characterized by myocyte
proliferation remains to be determined.
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Increases in the number of myocytes in the overloaded rat heart vary from 20% to 45%.86 89 118 These values are lower than those detected in humans but may be influenced by the simultaneous occurrence of myocardial damage and cell death. Myocyte loss complicates the estimation of the real number of newly formed myocytes in the ventricle; myocyte loss results in an underestimation of myocyte cellular hyperplasia, whereas myocyte hyperplasia leads to an underestimation of the magnitude of myocyte death in the myocardium. Thus, myocyte proliferation may be obscured by myocyte loss, and the measurement of cell number may not provide evidence of cell regeneration. This seems to be the case in the failing left ventricle of rats after coronary artery constriction86 and of dogs after ventricular pacing.81 139 Prolonged systemic hypertension in rats is associated with cellular hyperplasia142 143 in spite of diffuse tissue injury.143
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IGF-1 and Myocyte Growth |
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TopTerminally Differentiated CellsHistory of the Terminally...Postnatal Myocardial GrowthAging of the MyocardiumHeart FailureIGF-1 and Myocyte GrowthReferences |
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Several studies from our laboratory have raised the possibility that the reentry of myocytes into the cell cycle occurs in the adult rat heart in the presence of cardiac failure.86 118 143 Such a response of the overloaded heart is characterized by the stimulation of IGF-1 and IGF-1 receptors in the cells, which precedes the expression of late growth-related genes, DNA replication, myocyte nuclear mitotic division, and cell division.86 137 138 144 Moreover, the quantity of cyclins E, A, and B and cyclin-dependent kinases, cdk2 and cdc2, is enhanced in combination with their associated histone H1 kinase activity.145 These latter observations are consistent with the contention that myocytes can synthesize nuclear proteins, modulating the progression of these cells through the cell cycle and mitosis. Conversely, the suggestion has been made that cyclin A disappears during early postnatal life in the rat, becoming undetectable by day 14 after birth.146 Such a phenomenon has been implicated in the permanent withdrawal of myocytes from the cell cycle. The discrepancy between these results is difficult to explain, because the lack of this cyclin has been claimed after analyzing tissue samples that contain fibroblasts and endothelial cells that actively proliferate with maturation.73 Additionally, numerous reports have shown the persistence of low levels of DNA replication in adult myocytes.73 74 75 Attenuation of the IGF-1–IGF-1 receptor autocrine system in the cells appears to be coupled with the decline in myocyte proliferation with cardiac development.73 147
The in vivo results suggesting a potential link between IGF-1 and multiplication of myocytes have not been paralleled by similar observations in vitro. Culture studies of adult myocytes have documented that IGF-1 activates DNA synthesis148 149 and the expression of structural proteins, which are consonant with a hyperplastic and hypertrophic response of these cells.148 Moreover, IGF-1 increases the formation of myofibrils only in long-term cultures of matured myocytes.150 When myocytes surviving an acute myocardial infarction are stimulated by IGF-1 in vitro, the quantities of cyclin D1, E, A, and B are upregulated, and this adaptation may reflect the increase in IGF-1 receptors on the cells.149 Cyclin D1, E, and A kinase activity also increases, but cyclin B kinase activity is not enhanced by IGF-1. Concurrently, DNA replication in myocyte nuclei is detected, whereas mitotic division is not observed. Several phenomena may be involved in this block of the cell cycle in vitro. Myocardial loading may be critical for the progression of myocytes through mitosis, and mechanical forces are abolished in culture. Alternatively, other growth factors may be implicated in combination with IGF-1 in the regulation of mitosis in this cell population.
To characterize more directly the growth-promoting effect of IGF-1 on
myocytes in vivo, transgenic mice have been obtained in which the cDNA
for the human IGF-1B was placed under the control of a rat 
-myosin
heavy chain promoter.68 In mice heterozygous for
the transgene, the aggregate number of myocytes in the heart is
identical to that in nontransgenic littermates at birth but increases
21%, 31%, and 55% at 45, 75, and 210 days of age (Figure 7). This increase in cell number involves
mostly binucleated myocytes. By use of confocal microscopy, the average
volume of mononucleated, binucleated, trinucleated, and tetranucleated
myocytes has been measured for the first time. Overexpression of IGF-1
appears to have no influence on cell volume, further suggesting that
this growth factor sustains cell division in myocytes of the adult
heart. These results are in contrast with the contention that IGF-1
induces only cellular hypertrophy in vivo in the overloaded
heart.151 152 153 This conclusion has been reached
in the absence of any measurements of myocyte volume and number or of
indices of cell proliferation. Importantly, mice overexpressing IGF-1
characteristically show an attenuation in ventricular
dilation and myocardial loading after
infarction,154 but whether this beneficial effect
is mediated by the increased number of ventricular myocytes
and/or reduction of myocyte death in the surviving
myocardium remains to be determined.
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Acknowledgments |
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This study was supported by grants HL-38132, HL-39902, HL-43023, and AG-15746 from the National Institutes of Health and by a Grant-in-Aid from the American Heart Association (No. 950321). The expert technical assistance of Maria Feliciano is greatly appreciated.
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Footnotes |
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Reprint requests to Piero Anversa, MD, Department of Medicine, Vosburgh Pavilion, Room 302A, New York Medical College, Valhalla, NY 10595.
Received September 25, 1997; accepted April 8, 1998.
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A. Leri, Y. Liu, X. Wang, J. Kajstura, A. Malhotra, L. G. Meggs, and P. Anversa Overexpression of Insulin-Like Growth Factor-1 Attenuates the Myocyte Renin-Angiotensin System in Transgenic Mice Circ. Res., April 16, 1999; 84(7): 752 - 762. [Abstract] [Full Text] [PDF]
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P. H. Sugden Signaling in Myocardial Hypertrophy : Life After Calcineurin? Circ. Res., April 2, 1999; 84(6): 633 - 646. [Full Text] [PDF]
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A. Leri, L. Barlucchi, F. Limana, A. Deptala, Z. Darzynkiewicz, T. H. Hintze, J. Kajstura, B. Nadal-Ginard, and P. Anversa Telomerase expression and activity are coupled with myocyte proliferation and preservation of telomeric length in the failing heart PNAS, July 17, 2001; 98(15): 8626 - 8631. [Abstract] [Full Text] [PDF]
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K. B. S. Pasumarthi, S.-C. Tsai, and L. J. Field Coexpression of Mutant p53 and p193 Renders Embryonic Stem Cell-Derived Cardiomyocytes Responsive to the Growth-Promoting Activities of Adenoviral E1A Circ. Res., May 25, 2001; 88(10): 1004 - 1011. [Abstract] [Full Text] [PDF]
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