Background The scarring of the heart that results from myocardialinfarction has been interpreted as evidence that the heart iscomposed of myocytes that are unable to divide. However, recentobservations have provided evidence of proliferation of myocytesin the adult heart. Therefore, we studied the extent of mitosisamong myocytes after myocardial infarction in humans.
Methods Samples from the border of the infarct and from areasof the myocardium distant from the infarct were obtained from13 patients who had died 4 to 12 days after infarction. Tennormal hearts were used as controls. Myocytes that had enteredthe cell cycle in preparation for cell division were measuredby labeling of the nuclear antigen Ki-67, which is associatedwith cell division. The fraction of myocyte nuclei that wereundergoing mitosis was determined, and the mitotic index (theratio of the number of nuclei undergoing mitosis to the numbernot undergoing mitosis) was calculated. The presence of mitoticspindles, contractile rings, karyokinesis, and cytokinesis wasalso recorded.
Results In the infarcted hearts, Ki-67 expression was detectedin 4 percent of myocyte nuclei in the regions adjacent to theinfarcts and in 1 percent of those in regions distant from theinfarcts. The reentry of myocytes into the cell cycle resultedin mitotic indexes of 0.08 percent and 0.03 percent, respectively,in the zones adjacent to and distant from the infarcts. Eventscharacteristic of cell division — the formation of themitotic spindles, the formation of contractile rings, karyokinesis,and cytokinesis — were identified; these features demonstratedthat there was myocyte proliferation after myocardial infarction.
Conclusions Our results challenge the dogma that the adult heartis a postmitotic organ and raise the possibility that the regenerationof myocytes may contribute to the increase in muscle mass ofthe myocardium.
Myocyte replication occurs in the failing human heart,1 andthis form of cell growth tends to compensate for the exhaustionof myocyte hypertrophy.2 In chronic heart failure, myocytesat most double in size, and when this limit has been reachedno further enlargement of the heart occurs.2,3 For decades,it has been doubted whether the heart can grow by multiplicationof myocytes.4 The demonstration that the adult human brain containsa population of cells that are able to regenerate neurons5 hasnot prompted a comprehensive reexamination of the notion thatthe heart is a postmitotic organ,6 even though cardiac endothelialcells, smooth-muscle cells, and fibroblasts are known to proliferate.3,4Recently, a myocyte mitotic index (the ratio of the number ofnuclei undergoing mitosis to the number not undergoing mitosis)of 0.015 percent was measured in explanted hearts from patientsin the terminal stages of cardiac decompensation.1 The importanceof these results was questioned on the assumption that thislevel of myocyte replication has no clinical significance.4In the absence of supporting evidence, it has been claimed thatrates of myocyte proliferation ranging from 0.05 to 0.1 percentwould be required for meaningful therapeutic reconstitutionof damaged myocardium.4
Although a mitotic index of 0.015 percent, if sustained, couldresult in the formation of 100 g of myocardium in less thanthree months,1 the fraction of mitotic myocytes in patientswith late cardiac failure may reflect the ultimate growth reserveof this cell population. The mechanical overload in a diseasethat lasts several years may progressively exhaust the replicativecapacity of myocytes. Cells cannot divide indefinitely. In contrast,after extensive myocardial infarction, abrupt increases in theneed for growth may cause more myocytes to reenter the cellcycle than during chronic heart failure. To test this hypothesis,we determined the percentages of cycling myocytes and the mitoticindexes in patients who had died within a short time after extensivemyocardial infarction. Cycling myocytes were identified by theexpression of Ki-67 in nuclei. This nuclear protein is associatedonly with cell division.7,8 Although the function of Ki-67 isnot clear, it appears to promote cell proliferation by interferingwith the binding of p53 to DNA.9 To avoid errors in the identificationof myocytes, we assessed mitotic divisions of myocyte nucleiby confocal microscopy of immunolabeled cell cytoplasm.1,3 Themeasures of cell regeneration were determined separately inareas bordering on and distant from the infarcts. To investigatecharacteristics of cell division in vivo, we searched for theformation of the mitotic spindle by microtubules10 and of thecontractile ring by actin accumulation,11 as well as karyokinesisand cytokinesis.
Methods
Patients
Thirteen hearts were obtained from patients who had died 4 to12 days after myocardial infarction. There were seven men andsix women, with a mean (±SD) age of 64±15 years.As previously described,12 we obtained 10 control hearts atautopsy from five men and five women, with a mean age of 61±20years, who had died from causes other than cardiovascular disease.Infarct size was determined by measuring the area of grosslydetectable necrotic myocardium within the left ventricular freewall; this was expressed as a fraction of the total area.13The rest of the left ventricular free wall was divided intothree equal parts, which were defined as the border zone, theintermediate region, and the distant myocardium. Since the averagesize of the infarct was 35 percent, the average size of eacharea of viable tissue was nearly 20 percent of the left ventricularfree wall. Samples were obtained only from the border zone andthe distant myocardium. Tissue specimens from comparable areasof noninfarcted control hearts were examined.
Confocal Microscopy and Immunocytochemical Analysis
The specimens were fixed in 10 percent phosphate-buffered formalinand embedded in paraffin. The histologic sections were stainedwith propidium iodide (10 µg per milliliter) and antibodyto -sarcomeric actin (clone 5C5, Sigma), diluted 1:20 in phosphate-bufferedsaline. For identification of mitotic spindles, the sampleswere exposed to a mouse monoclonal antitubulin antibody (Zymed).Fluorescein isothiocyanate–conjugated antimouse IgG wasused as a secondary antibody. For the detection of Ki-67, thesamples were exposed for one hour at 37°C to a mouse monoclonalantibody against Ki-67 (clone MIB-1, Diagnostic Biosystems),diluted 1:40 in phosphate-buffered saline.7 Fluorescein isothiocyanate–conjugatedantimouse IgG was again used as a secondary antibody. Subsequently,specimens were processed for confocal microscopy1,3 and examinedwith a confocal microscope (MRC-1000, Bio-Rad).
Statistical Analysis
The numbers of myocyte nuclei labeled by Ki-67 were determinedby evaluating approximately 3000 nuclei in the border zone and9000 to 11,000 nuclei in the distant myocardium of each infarctedheart. Approximately 100,000 to 125,000 nuclei were evaluatedin each control heart. The numbers of myocyte nuclei undergoingmitosis were determined by evaluating an average of 80,000 nucleiin the border zone and 104,000 nuclei in the distant myocardiumof each infarcted heart. The values in corresponding anatomicalareas of the control hearts were 100,000 and 110,000. Samplingfor mitoses was larger than sampling for Ki-67 because of thelower frequency of mitoses in the myocardium. A total of 1165Ki-67–positive myocyte nuclei was counted in infarctedhearts. This yielded an overall sampling error of 2.9 percent(the sampling error equals the square root of n divided by n,where n equals the total count). The number of myocyte nucleiundergoing mitosis was 590, reflecting a 4.1 percent samplingerror.14 These values are less than the biologic variabilityamong humans, which is at least 20 percent.14 Since the numbersof Ki-67–labeled nuclei and mitotic images were similarin these two control regions analogous to border and distantmyocardium in infarcted heart, separate measurements were combinedto generate a single value. The results are presented as means±SD. The significance of the differences was determinedwith the use of Student's t-test for comparisons of two valuesand the Bonferroni method for multiple comparisons.15
Results
Patients
The hearts of the 13 patients with myocardial infarction wereobtained 7 to 17 hours after death. Coronary atherosclerosiswas severe and affected the left and right coronary arteriesin all cases. Myocardial infarction consistently involved theanterior and inferior aspects of the left ventricle and wasassociated with cardiac rupture in three subjects. The sizeof the infarct ranged from 26 to 44 percent, averaging 35±7percent. In three cases, an old fibrotic infarct was noted,and foci of replacement fibrosis and areas of interstitial fibrosiswere identified in all three of these hearts. None of the patientshad a history of systemic hypertension or diabetes. Two of the13 patients had been treated with thrombolytic agents. The averageweight of the hearts with myocardial infarction was 497±129 g, and that of the control hearts was 361±51 g (P=0.005).The control hearts were from subjects of similar age who didnot have primary heart disease or major risk factors for coronaryartery disease, including hypertension, diabetes, obesity, andsevere atherosclerosis. Autopsy and histologic examination ofall organs ruled out the presence of diffuse metastatic malignantneoplasms and chronic inflammation. Six patients died from acutetrauma, one from gastrointestinal hemorrhage, two from cerebralhemorrhage, and one from pulmonary thromboembolism.
Ki-67 Labeling and Mitotic Index
Ki-67 is a nuclear antigen expressed in all phases of the cellcycle except G0.7 Ki-67 is apparent mainly in the late S phase,increases further in G2, persists during prophase and metaphase,7and decreases in anaphase and telophase. Ki-67 is preferableto thymidine, bromodeoxyuridine, and proliferating-cell nuclearantigen for labeling, because it is not involved in DNA repair.16Expression of Ki-67 is a requirement for cells to traverse thecell cycle and undergo cell division.7,8 All types of proliferatinghuman cells express Ki-67.16,17 Ki-67 was measured in myocytenuclei of control and infarcted hearts by confocal microscopy(Figure 1A, Figure 1B, Figure 1C, and Figure 1D).1,3,18,19 Incomparison with myocytes from normal hearts, the number of Ki-67–positivenuclei in myocytes from hearts with myocardial infarction was84 times as high in samples from the border zone and 28 timesas high in samples from the distant myocardium (P<0.001 forboth comparisons) (Figure 1E).
Figure 1. Ki-67 Labeling of Cycling Myocytes in an Infarcted Heart.
In Panels A and C, green fluorescence documents localization of Ki-67 in nuclei (arrows and arrowhead). In Panels B and D, red fluorescence shows staining of myocyte cytoplasm by sarcomeric -actin antibody, and bright fluorescence shows labeling of myocyte nuclei (arrows) and nonmyocyte nuclei (arrowhead) by a combination of propidium iodide and Ki-67. Ki-67 labeling of a myocyte nucleus in metaphase is evident in Panels C and D (double arrows). Panels A and B show cells from the border zone, and Panels C and D cells from the distant myocardium. (Panels A, B, C, and D, x800.) Panel E shows the effects of infarction on the mean (±SD) number of Ki-67–labeled myocyte nuclei. The asterisks indicate P<0.001 for the comparison between the infarcted hearts and the control hearts; the dagger indicates P<0.001 for the comparison between the distant myocardium and the border zone in the infarcted hearts.
Although the expression of Ki-67 in myocytes after infarctionby itself challenges the assumption that the heart is a postmitoticorgan,4,6,20 we found further evidence of myocyte division.During mitosis, microtubules form the mitotic spindle, allowingeach chromatid to be pulled toward the spindle pole by the kinetochoremicrotubules. This process occurs in anaphase and lasts onlya few minutes.21 The arrangement of microtubules in the mitoticspindle of dividing myocytes was detected on microscopical examination(Figure 2). In addition, accumulation of actin and its assemblyin the contractile ring were identified with the use of sarcomeric-actin antibody (Figure 3). Myocyte division was in the processof completion and actin was condensed in a narrow region, delineatinga groove between the two forming daughter cells. Images of nuclearmitotic division (Figure 4) and cytokinesis (Figure 5) werealso obtained, strengthening the notion that Ki-67 labelingin nuclei represents multiplying myocytes.
Figure 2. Identification of Mitotic Spindles in Dividing Myocytes from Infarcted Hearts (x2000).
In Panel A, blue fluorescence indicates the organization of tubulin in the mitotic spindle (arrows). Panel B depicts a nucleus in metaphase, indicated by the green fluorescence of propidium iodide (arrowheads). In Panel C, green and blue fluorescence shows the combination of tubulin and metaphase chromosomes (arrows and arrowheads). Panel D shows staining of myocyte cytoplasm by antibody against sarcomeric -actin (red fluorescence), tubulin labeling (blue fluorescence), and chromosomes in metaphase (green fluorescence) (arrows and arrowheads).
Figure 3. A Myocyte in the Process of Cytokinesis.
Accumulation of actin (arrows) in the region of cytoplasmic division and cell separation is shown; red fluorescence shows staining of myocyte cytoplasm by antibody against sarcomeric -actin, and green fluorescence shows propidium iodide labeling of chromosomes (x2000).
Figure 4. Mitotic Myocyte Nuclei in Infarcted Hearts.
Panels A, B, and C demonstrate the combination of labeling of myocyte cytoplasm by antibody against sarcomeric -actin (red fluorescence) and staining of metaphase chromosomes by propidium iodide (green fluorescence). (Panels A and B, x1200; Panel C, x2000.)
Figure 5. Myocyte Cytokinesis in Infarcted Hearts (x1500).
Cytokinesis is shown in Panels A and B by the combination of labeling of nuclei by propidium iodide (green fluorescence) and staining of myocyte cytoplasm by antibody against sarcomeric -actin (red fluorescence). The divided nuclei mirror each other in the newly formed myocytes.
As a direct quantitative estimate of the extent of myocardialrepair, we calculated a myocyte mitotic index. Staining withantibody to sarcomeric -actin is specific for I bands of cardiacand skeletal muscle cells and does not affect other actin isoforms.22Therefore, the distinction between myocyte and nonmyocyte nucleiis extremely simple: interstitial cells are not stained by -sarcomericactin, and only their nuclei can be seen on staining with propidiumiodide (Figure 2D, Figure 4A, Figure 4B, Figure 4C, and Figure 5B).The same approach was used for Ki-67 labeling (Figure 1Band Figure 1D). Myocyte mitotic indexes are shown in Figure 6.In comparison with normal hearts, hearts with myocardialinfarction have 70 times as many myocytes undergoing mitosisin the border zone and 24 times as many in the distant myocardium(P<0.001 for both comparisons). The fact that the value was2.9 times as high in the border zone as in the distant myocardium(P<0.001) is consistent with the higher level of Ki-67 expressionin the border zone.
Figure 6. Effects of Infarction on the Mean (±SD) Number of Mitotic Myocytes.
The asterisks indicate P<0.001 for the comparison between the infarcted hearts and the control hearts; the dagger indicates P<0.001 for the comparison between the distant myocardium and the border zone in the infarcted hearts.
Discussion
Our results indicate that the adult heart has a subpopulationof myocytes that are not terminally differentiated; these myocytesevidently reentered the cell cycle and underwent nuclear mitoticdivision early after infarction. The number of cycling myocyteswas significantly larger in the zone bordering the infarct thanin the distant myocardium. In laboratory animals, conditionsthat mimic coronary artery disease are characterized by DNAreplication and myocyte division.3,23 These responses peak 7to 14 days after coronary-artery restriction and decrease withtime.23 A similar phenomenon may occur in humans, suggestingthat prolonged heart failure may progressively affect the mitoticactivity of myocytes. Multiplication of myocytes is markedlyattenuated as the length of time after myocardial infarctionincreases.1
DNA synthesis in myocyte nuclei has been measured experimentallyon the basis of incorporation of nucleotides such as [3H]thymidineand bromodeoxyuridine or labeling by proliferating-cell nuclearantigen, which is implicated in the transition from G1 to Sphase.3,4,20,24 However, these findings have been questionedas indicators of cell proliferation.3,4 The detection of myocytenuclei that are positive for thymidine and bromodeoxyuridinedoes not indicate whether DNA synthesis is coupled with nuclearhyperplasia, ploidy formation, or DNA repair. Furthermore, thymidineand bromodeoxyuridine cannot be injected into humans exceptin unusual circumstances.25 Limitations apply to staining ofproliferating-cell nuclear antigen in cell nuclei. Proliferating-cellnuclear antigen is a cofactor of DNA polymerase , which is implicatedin DNA synthesis, cell-cycle progression, and DNA repair.7 Thelast property may explain only in part the high level of expressionof this protein in the nuclei of myocytes in terminally decompensatedhuman hearts.26 In fact, the reported values most likely overestimatedthe actual number of replicating myocytes. We overcame thesedifficulties by using Ki-67 as a marker of cell proliferation.There is not a single example of a Ki-67–positive cellthat cannot divide.7,8,9,16,17 Biochemically, Ki-67 is an essentialelement of the outer dense fibrillar compartment of the nucleolus,where it acts as an efficiency factor in the rapid productionof ribosomes for the increased metabolic requirements of dividingcells.8 Structurally, Ki-67 is a molecule of 395 kd that containsa motif typical of several transcription factors.27 Ki-67 hasa preference for binding to adenine- and thymidine-rich sequencessimilar to the consensus site of p53.9 This competition emphasizesthe role of Ki-67 in cell replication.
The observation that mitotic indexes of nearly 800 and 300 myocytenuclei per 106 cells characterize the acute myocardial responseto infarction raises some crucial questions. The infarcted heartis frequently discussed as proof of the inability of myocytesto reenter the cell cycle and reconstitute muscle mass.6,20However, myocytes in the infarcted area die in a few hours,and ischemic damage occurs in the vascular and nonvascular componentsof the interstitium.13 The formation of new myocardium in theinfarcted region by myocyte growth alone is impossible. We foundthat mitotic activity occurred in myocytes in the border zoneand the more distant myocardium, where tissue oxygenation waslargely maintained.28 The possibility that karyokinesis wasnot followed by myocyte cytokinesis is unlikely. Unlike themyocytes of rodents and dogs,23,29,30 ventricular myocytes inhumans are predominantly mononucleated.31 Studies of dissociatedmyocytes from 72 normal hearts, 81 hearts with hypertrophy,and 95 hearts with ischemic cardiomyopathy, from subjects rangingfrom 26 to 93 years of age, found that mononucleated myocytesconstituted 75 percent and binucleated cells 25 percent of thecell population. This proportion was not affected by disease,age, or sex.31 However, this finding does not exclude the possibilitythat some binucleation of myocytes occurred after infarction.
Measurements of the proportion of myocytes in the cell cycleby labeling of Ki-67 and expression of the proportion of mitoticmyocytes by means of the mitotic index indicate a consistentrelation between these two markers of cell growth. The numberof cycling myocytes is nearly 50 times as high as the numberof mitotic myocytes in both normal and infarcted hearts. Sincemitosis is completed in about 30 minutes,32 the duration ofthe myocyte cell cycle in vivo should be approximately 25 hours.The normal left ventricle contains 5.5x109 myocytes, and thisvalue decreases to an average of 3.8x109 after myocardial infarction.33A mitotic index of 11 myocytes per 106 in the intact ventricleand 520 myocytes per 106 in the injured ventricle (775 myocytesper 106 in the border zone and 264 myocytes per 106 in the distantmyocardium; mean, 520 myocytes per 106) implies that 60,500myocytes are in mitosis in the normal left ventricle and 1,976,000in the infarcted left ventricle. If the level of proliferationmeasured up to 12 days after coronary-artery occlusion persisted,the 1.7x109 myocytes lost as a result of infarction would bereplaced in 18 days (myocytes per day, 1.98x106x48=95x106; myocytesper 18 days, 95x106x18=1.7x109). This calculation assumes thatmitosis lasts 30 minutes (24 hours=48 half-hours) and that replicatingmyocytes divide only once during this period.
A relevant issue is the origin of cycling myocytes in normaland diseased hearts. These proliferating cells could derivefrom resident cardiomyocytes or from circulating stem cellsthat reach the spared myocardium after infarction. However,in the absence of stimulation by several cytokines, the numberof circulating stem cells is very low.34,35,36 Moreover, circulatingstem cells move to the area of injury36 without infiltratingthe viable tissue.37 Recently, we showed that bone marrow–derivedstem cells, injected into the border of a myocardial infarct,homed to the infarcted zone and did not move into the remainingnonaffected portion of the ventricular wall.37 Injury and largenumbers of stem cells seem to be required for these cells' migration,multiplication, and differentiation into the cell lineages ofthe damaged heart or other organs.37,38
Although a cardiac stem cell has not yet been identified, suchprimitive undifferentiated cells may be present, and the dividingmyocytes may be their progeny. This phenomenon occurs in thebrain.5,36 As in the damaged brain,36 repair of the necroticmyocardium may involve interventions that promote the migrationof endogenous, exogenous, or both types of stem cells to theinfarcted region. Whether this therapeutic approach is superiorto transplantation of myoblasts39 or fetal cardiomyocytes40remains an important question. Hypertrophy and proliferationof myocytes do not prevent ventricular remodeling and the onsetand evolution of cardiac failure after severe ischemic injury.Restoration of the infarcted myocardium, even in part, mightinterfere with the progression of the structural and functionalalterations of the diseased heart,37 thus delaying irreversibleventricular dysfunction.
In summary, our results challenge the dogma that the heart isa postmitotic organ. Myocyte proliferation may be a componentof the growth reserve of the human heart; this mechanism couldreplace damaged myocardium. The presence of cell division inthe nondiseased part of the heart suggests a continuous turnoverof cells during the life span of the organism. The belief thatmyocardial infarction constitutes the most obvious demonstrationof the incapacity of ventricular myocytes to replicate mustbe reconsidered.
Supported by grants (HL-38132, HL-39902, HL-43023, AG-15756,HL-65577, HL-66923, and AG-17042) from the National Institutesof Health.
This article is dedicated to the memory of Giorgio Olivetti,M.D., late professor and chairman of the Department of Pathology,University of Parma, Parma, Italy.
Source Information
From the Department of Medicine, New York Medical College, Valhalla (A.P.B., K.U., J.K., B.N.-G., A.L., P.A.); the Department of Pathology, University of Udine, Udine, Italy (S.-M.Y., N.F., C.A.B.); and the Department of Pathology, University of Trieste, Trieste, Italy (R.B., F.S.).
Address reprint requests to Dr. Anversa at the Department of Medicine, Vosburgh Pavilion, Rm. 302, New York Medical College, Valhalla, NY 10595, or at piero_anversa{at}nymc.edu.
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[Abstract][Full Text]
-sarcomeric actin (clone 5C5, Sigma), diluted 1:20 in phosphate-buffered saline. For identification of mitotic spindles, the samples were exposed to a mouse monoclonal antitubulin antibody (Zymed). Fluorescein isothiocyanate–conjugated antimouse IgG was used as a secondary antibody. For the detection of Ki-67, the samples were exposed for one hour at 37°C to a mouse monoclonal antibody against Ki-67 (clone MIB-1, Diagnostic Biosystems), diluted 1:40 in phosphate-buffered saline.7 Fluorescein isothiocyanate–conjugated antimouse IgG was again used as a secondary antibody. Subsequently, specimens were processed for confocal microscopy1,3 and examined with a confocal microscope (MRC-1000, Bio-Rad). 
, which is implicated in DNA synthesis, cell-cycle progression, and DNA repair.7 The last property may explain only in part the high level of expression of this protein in the nuclei of myocytes in terminally decompensated human hearts.26 In fact, the reported values most likely overestimated the actual number of replicating myocytes. We overcame these difficulties by using Ki-67 as a marker of cell proliferation. There is not a single example of a Ki-67–positive cell that cannot divide.7,8,9,16,17 Biochemically, Ki-67 is an essential element of the outer dense fibrillar compartment of the nucleolus, where it acts as an efficiency factor in the rapid production of ribosomes for the increased metabolic requirements of dividing cells.8 Structurally, Ki-67 is a molecule of 395 kd that contains a motif typical of several transcription factors.27 Ki-67 has a preference for binding to adenine- and thymidine-rich sequences similar to the consensus site of p53.9 This competition emphasizes the role of Ki-67 in cell replication. 
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