(Circulation. 1999;99:1426-1434.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Cell Death in Acromegalic Cardiomyopathy
From the Departments of Cardiology and Endocrinology, Sacred Heart Catholic University, Rome, Italy (A.F., C.C., S.C., F.C., A.M.); and the Department of Medicine, New York Medical College, Valhalla, NY (M.S., S.G., A.L., J.K., P.A.).
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Abstract |
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Background—Prolonged untreated acromegaly leads to a nonspecific myopathy characterized by ventricular dysfunction and failure. However, the mechanisms responsible for the alterations of cardiac pump function remain to be defined. Because cell death is implicated in most cardiac disease processes, the possibility has been raised that myocyte apoptosis may occur in the acromegalic heart, contributing to the deterioration of ventricular hemodynamics.
Methods and Results—Ten acromegalic patients with diastolic dysfunction and 4 also with systolic dysfunction were subjected to electrocardiography, Holter monitoring, 2-dimensional echocardiography, cardiac catheterization, and biventricular and coronary angiography before surgical removal of a growth hormone–secreting pituitary adenoma. Endomyocardial biopsies were obtained and analyzed quantitatively in terms of tissue scarring and myocyte and nonmyocyte apoptosis. Myocardial samples from papillary muscles of patients who underwent valve replacement for mitral stenosis were used for comparison. The presence of apoptosis in myocytes and interstitial cells was determined by confocal microscopy with the use of 2 histochemical methods, consisting of terminal deoxynucleotidyl transferase (TdT) assay and Taq probe in situ ligation. Acromegaly was characterized by a 495-fold and 305-fold increase in apoptosis of myocytes and nonmyocytes, respectively. The magnitude of myocyte apoptosis correlated with the extent of impairment in ejection fraction and the duration of the disease. A similar correlation was found with the magnitude of collagen accumulation, indicative of previous myocyte necrosis. Myocyte death was independent from the hormonal levels of growth hormone and insulin-like growth factor-1. Apoptosis of interstitial cells did not correlate with ejection fraction.
Conclusions—Myocyte cell death, apoptotic and necrotic in nature, may be critical for the development of ventricular dysfunction and its progression to cardiac failure with acromegaly.
Key Words: cells • heart failure • growth substances • cardiomyopathy
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Introduction |
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Growth hormone (GH) excess leads to cardiovascular alterations whose underlying cause remains controversial. Hypertension, glucose intolerance, or chronic exposure to GH may alone be implicated in the abnormalities of ventricular hemodynamics.1 2 Heart failure, involving both the left and right ventricles, may occur late in acromegaly,3 but the events implicated in the progressive deterioration of pump performance have not been identified. Myocardial hypertrophy and cavitary dilation are consistent findings.4 Focal areas of replacement fibrosis and diffuse interstitial fibrosis, in combination with muscle fiber disarray, lymphocyte infiltrates, and small vessel disease have been described,3 4 but the amount of healthy myocardium largely predominates, raising questions on the underlying basis responsible for the impairment in the functional capacity of the acromegalic heart. Recent observations have indicated that ongoing myocyte cell death, apoptotic in nature, affects the decompensated human heart.5 6 Programmed cell death is not associated with collagen deposition,7 which typically follows cell necrosis.8 Additionally, myocyte apoptosis is scattered across the wall and, rarely, involves groups of 2 to 3 cells. This form of cell death can be triggered by humoral factors9 and physical forces10 11 and has a significant impact on myocardial mechanics by reducing the force-generating capacity of the muscle.10 The ability of developing comparable degrees of resting tension with changes in sarcomere length is also altered; the Frank-Starling relation is severely modified by myocyte apoptosis of <0.4%.10 12 These physiological deficiencies are accompanied by restructuring of the wall with side-to-side slippage of myocytes, mural thinning, and cavitary dilation.13 Therefore, the possibility may be advanced that programmed myocyte cell death occurs in the acromegalic heart, playing a key role in the deterioration of function with time. This hypothesis was tested with the use of cardiac biopsies from the left and right ventricular myocardium of patients with acromegaly.
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Methods |
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Patients
Ten patients, 5 men and 5 women, with active acromegaly and cardiac dysfunction, varying from New York Heart Association class II to IV, were studied. All patients underwent noninvasive cardiac examinations consisting of ECG, 2-dimensional echocardiography with Doppler analysis, and Holter monitoring. Invasive studies consisting of cardiac catheterization, coronary angiography, and ventricular endomyocardial biopsy also were performed. Echocardiography included the measurement of left ventricular end-systolic and end-diastolic diameters and the evaluation of the thickness of the septum and the posterior aspect of the left ventricular wall. Systolic function was assessed by the analysis of left ventricular ejection fraction (EF), whereas diastolic function was determined by the E/A ratio. Left ventricular mass was derived with the use of the echocardiographic method described by Devereux and Reichek14 and, subsequently, normalized by body surface area to obtain a left ventricular mass index. These parameters were collected before surgical removal of a GH-secreting pituitary adenoma. Samples from papillary muscles of 10 patients of comparable age and sex who underwent valve replacement for mitral stenosis were used for comparison. Although these were not healthy individuals, their papillary muscles were not overloaded. However, some unloading caused by the stenosis was present. Despite this limitation, a more appropriate control myocardium could not be obtained. This study was approved by the institutional review committee, and patients gave informed consent. Procedures followed were in accordance with institutional guidelines.
Hormone Levels
Plasma levels of GH were measured in duplicate by an
immunoradiometric assay kit (hGH-IRMA-CT, Radim). Similarly,
insulin-like growth factor-1 (IGF-1) concentration was assessed by
radioimmunoassay (Medgenix Diagnostics). Levels of GH and
IGF-1 were expressed as mean values obtained by averaging the results
from 4 daily blood samples taken at 8:00 AM and noon and at
5:00 and 11:00 PM.
Light Microscopy
In acromegalic patients, 3 to 4
endomyocardial biopsies, 
3
mm3 each, were collected from the septal apical
region of the right and left ventricle. Specimens of papillary muscles
from patients with mitral stenosis were used for comparison.
Tissue was fixed in 10% formalin, paraffin-embedded, and stained with
hematoxylin-eosin or trichrome. Myocardial fibrosis was measured with
the use of a computer-assisted image analyzer with KS-300
software (Zeiss). A total of 24 serial sections were examined in each
patient.
Confocal Microscopy
Sections were incubated in a solution containing 5 U of terminal
deoxynucleotidyl transferase (TdT)
(Boehringer Mannheim), 2.5 mmol/L
CoCl2, 0.2 mol/L potassium cacodylate, 25
mmol/L Tris-HCl, 0.25% BSA, and 0.5 nmol/L biotinylated 2'
deoxyuridine-5'-triphosphate (biotin-16-dUTP). After exposure to 5
µg/mL of FITC-labeled extravidin, samples were stained with
-sarcomeric actin antibody (clone 5C5, Sigma Chemical Co) and then
with TRITC-labeled anti-mouse IgG. Nuclei were visualized with the use
of propidium iodide (20 µg/mL). Apoptosis was evaluated by
use of confocal microscopy (MCR-1000, Bio-Rad) to analyze
chromatin alterations and the histochemical detection of double DNA
strand breaks. A minimum of 3.42 mm2 to a
maximum of 9.88 mm2 of
myocardium was analyzed in each sample by TdT. The
average numbers of myocyte nuclei and nonmyocyte nuclei
examined to evaluate apoptosis in patients with acromegaly were
2621±1104 and 7315±2671, respectively. Corresponding values in
patients with mitral stenosis were 12 586±12 932 and
31 386±34 209. The numerical density of myocyte and
nonmyocyte nuclei was determined by counting the number of
propidium iodide–labeled nuclei included in -sarcomeric
actin-positive and -sarcomeric actin-negative cells. In acromegaly,
these values were 211±45 mm2 of tissue for
myocytes and 599±94 mm2 of
myocardium for nonmyocytes. In subjects with mitral
stenosis, these values were 277±45
mm2 for myocytes and 587±85 for
nonmyocytes. These parameters were used to compute
the number of TdT-stained apoptotic nuclei per
106 cells.6
Internucleosomal DNA cleavage was confirmed by in situ ligation15 because the TdT assay may overestimate the extent of cell death as a marker of apoptosis.15 Specifically, double-strand DNA fragments for in situ ligation to 3' overhangs were prepared with primers 5'-GTGGCCTGCCCAAGCTCTACCT-3' and 5'-GGCTGGTCTGCCGCCGTTTTCGACCCTG-3' complementary to pBluescript-bSDI1 plasmid. The reaction included 50 mmol/L Tris-HCl, pH 8.3, 10 mmol/L KCl, 1.5 mmol/L MgCl2, 16.6 µmol/L digoxigenin-11-dUTP (Boehringer Mannheim), 16.6 µmol/L TTP, 50 µmol/L of dATP, dCTP, and dTTP, 100 pmol of each primer, and 10 pg of plasmid. Taq polymerase (2.5 U) was added to the reaction mixture after heating to 80°C. Polymerase chain reaction was performed with 35 cycles of 20 seconds at 95°C, 20 seconds at 61°C, and 120 seconds at 74°C, the final cycle having an extension time of 4 minutes. Gel electrophoresis was performed to document a single polymerase chain reaction product. Amplified product was purified with the Qiagen kit. Digoxigenin-labeled fragments were ligated to DNA in tissue sections with the use of T4 ligase. Sections were treated with proteinase K (50 µg/mL PBS) for 30 minutes at 37°C, and a mixture of 50 mmol/L Tris-HCl, pH 7.8, 10 mmol/L MgCl2, 10 mmol/L DTT, 1 mmol/L ATP, 25 µg/mL BSA, 15% polyethylene glycol (8000 MW), 1 µg/mL probe, and 25 U/mL DNA T4 ligase was applied for 4 hours. Sections were washed with water at 70°C and incubated with anti-digoxigenin mouse monoclonal antibody (Boehringer Mannheim) followed by exposure to FITC-labeled goat anti-mouse IgG. Myocyte cytoplasm and nuclei were labeled as described in the TdT assay. Sections exposed to DNase I were used as positive control, whereas omission of T4 ligase was used as negative control. This methodology has previously been used in our laboratory.11 Essentially the same amount of myocardium indicated for TdT was examined by confocal microscopy in both groups of patients. The average numbers of myocyte and nonmyocyte nuclei analyzed by the Taq polymerase probe in acromegalic subjects were 3025±972 and 8922±1813, respectively. In cases with mitral stenosis, 13 561±14 229 and 30 032±32 070 myocyte and nonmyocyte nuclei were evaluated. The numerical density of myocyte and nonmyocyte nuclei was then determined. In acromegaly, values were 204±47 mm2 of tissue for myocytes and 616±92 mm2 of myocardium for nonmyocytes. Corresponding values with mitral stenosis were 285±39 mm2 and 568±65 mm2. On this basis, the number of Taq-positive apoptotic nuclei per 106 cells was computed.
Statistical Analysis
All tissue samples were coded, and the code was broken at the
end of the studies. Results are presented as mean±SD.
Statistical significance between 2 measurements was determined by the
2-tailed unpaired Student's t test; probability values
<0.05 were considered significant. Linear regression analysis
was performed to correlate duration of the disease and EF with the
magnitude of apoptosis in myocytes and interstitial
cells.16
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Results |
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Patients
Table 1
lists the sex, age,
duration of disease, and hormonal profile of the 10 patients included
in the current study. They consisted of 5 men, 53±14 years old, and 5
women, 57±4 years old, who had active acromegaly. Time from diagnosis
varied from 2 to 15 years and did not differ between the 2 groups: men,
6.0±5.6 years; women, 4.8±3.3 years (not significant). In men, the
levels of GH and IGF-1 were 12±5 ng/mL and 649±144 ng/mL,
respectively. Values in women were 26±17 ng/mL and 693±141 ng/mL.
Acromegaly was confirmed by the inability of an oral glucose load to
decrease the plasma concentration of GH. The normal upper limit for GH
is 5 ng/mL and for IGF-1, 300 ng/mL.17 With the exception
of 1 male patient, who received lanreotide and cabergoline treatment,
the other 9 individuals were not under medical therapy at the time of
cardiac biopsies.
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Cardiac Characteristics
The ECG showed signs of ventricular
hypertrophy in all cases. Rhythm defects were not observed
in 9 patients, but 1 individual, patient 2 in Table 1
, had left
bundle-branch block. Holter monitoring in this subject revealed
frequent ventricular ectopic beats with some doublets and
triplets. Phases of nonsustained ventricular
tachycardia were also detected. This patient was considered
to be in Lown class IVb. Anatomic and functional parameters
are listed in Table 2. In subjects with
mitral stenosis, the thickness of the septum and posterior
aspect of the left ventricular wall was 9.3±0.71 mm
and 9.0±0.58 mm, respectively. These values increased 33%
(P<0.001, 12.4±1.1 mm) and 32% (P<0.001,
11.9± 1.5 mm) in acromegalic subjects. However, comparable
changes in ventricular thickness were noted in acromegalic
men (12±1.9 mm) and women (11.8±1.0 mm). A similar
adaptation was also noted in septal thickness (men, 12.1±1.2 mm;
women, 12.6±1.1 mm). Left ventricular
end-diastolic diameter was within normal range in 9
patients, indicating that wall thickening exceeded the alteration in
chamber radius. However, a marked increase in cavitary volume was noted
in the subject with rhythm disturbances. Thus in 9 cases, mural
thickening was the prevailing response of the heart, resulting in an
increase in wall thickness-to-chamber radius ratio. Left
ventricular mass index in subjects with mitral
stenosis was 92±6 g/m2. With acromegaly,
this parameter was within normal range in 1 man (114
g/m2) but increased in other 4 men (213±85
g/m2) and 5 women (160±13
g/m2). No statistical difference was noted
between sexes. The average value in the entire population of 10
patients was 177±61 g/m2.
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EF was within normal limits (>50%) in 6 (56%±7%) but was reduced
in 4 (36%±10%) acromegalic individuals (P<0.01). The
average value of this parameter in the 10 patients was
48%±13%. Moreover, ventricular
contractility, assessed by ventriculography, was
compromised in these 4 subjects. Doppler evaluation of mitral flow
documented diastolic dysfunction in all patients because
the E/A ratio was consistently <1 (Table 2). Subjects
with mitral stenosis had an E/A ratio of 1.3±0.3, which
decreased 51% (P<0.001, 0.64±0.09) with acromegaly. Left
ventricular end-diastolic pressure was elevated
in all cases, varying from a minimum of 13 mm Hg to a maximum of
25 mm Hg, averaging 15±4 mm Hg. Control value is <12
mm Hg. Left ventricular systolic pressure was not
increased in acromegalic patients. Similarly, coronary
angiography did not detect defects in the arterial
tree.
Myocardial Structure
The amount of interstitial collagen in combination
with small foci of replacement fibrosis occupied 1.0%±0.5% of the
myocardium of subjects with mitral stenosis and
7.9%±4.7% of the tissue in acromegalic patients. This 8-fold
increase in the extent of connective tissue was statistically
significant (P<0.001). Comparable values were obtained in
acromegalic men (7.7%±5.8%) and women (8.1%±4.1%). The degree of
myocardial fibrosis was inversely correlated with the impairment in EF
(r=-0.92; P<0.0003) and positively correlated
with the duration of the disease (r=0.91;
P<0.0003). Myocytes appeared to be enlarged, and nuclei
were prominent and irregular in shape.
Myocyte and Interstitial Cell Apoptosis
Apoptosis was detected by 2 independent
histochemical methods, consisting of the TdT assay and in situ
ligation. Tissue sections were examined by confocal
microscopy.6 11 Figure 1, A
through C, illustrates a myocyte undergoing apoptosis; nuclear
damage with half-moon appearance is depicted by the red
fluorescence of propidium iodide staining. The presence of DNA
strand breaks is documented separately by the green
fluorescence of the TdT assay. The myofibrillar component of
the cytoplasm is shown by the red florescence of -sarcomeric actin
antibody labeling. Chromatin margination and loss in DNA, or nuclear
pyknosis, are demonstrated in Figure 2, A
through C and D through F. Similar nuclear modifications in
interstitial cells are depicted in Figures 3 and 4.
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Apoptosis was confirmed by a second method consisting of
Taq polymerase in situ ligation. This technique identifies
double-strand cleavage of the DNA with single-base 3' overhangs that
occur exclusively with apoptosis.15 Figure 5 illustrates 2 myocytes undergoing
apoptosis in 2 patients with acromegaly. Nuclear morphology,
which was largely preserved, is shown by the red fluorescence
of propidium iodide staining (Figure 5, A and D). Double-strand
DNA cleavage with single-base 3' overhangs is depicted by green
fluorescence in panels B and E. The combination of these 2
nuclear stainings with -sarcomeric actin antibody labeling of the
myocyte cytoplasm is represented in panels C and F. The
specificity of in situ ligation to recognize DNA damage was established
by exposing tissue sections to DNase I; diffuse staining of nuclei was
observed (positive control). Conversely, the omission of T4 ligase
resulted in the lack of labeling of nuclei (negative control).
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Low levels of myocyte apoptosis were present in samples
from patients with mitral stenosis. TdT assay yielded an
average value of 6.2±13 per 106 and
Taq 5.4±11 per 106. Corresponding
values in interstitial cells were 16±27 per
106 and 14±28 per 106.
With acromegaly, the TdT reaction showed values of 2810±2725 per
106 in myocytes and 4453±3665 per
106 in interstitial cells, whereas in
situ ligation demonstrated 2671±2469 per 106 in
myocytes and 4273±3592 per 106 in
interstitial cells. On the basis of TdT, acromegaly was
characterized by a 453-fold (P<0.005) and 278-fold
(P<0.002) increase in the number of myocytes and
nonmyocytes dying by apoptosis, respectively. With
Taq, apoptosis in acromegaly increased 495-fold
(P<0.004) and 305-fold (P<0.002) in myocytes
and interstitial cells. None of the small differences
between TdT and in situ ligation data were statistically significant.
The extent of apoptosis in acromegalic patients was obtained by
examining 8 right ventricular and 2 left
ventricular myocardial biopsies. When ejection fraction was
compared with the magnitude of apoptosis, it was apparent that
severe impairment in cardiac pump function was accompanied by higher
levels of myocyte death (Figure 6A).
Additionally, the duration of acromegaly correlated with the degree of
apoptosis (Figure 6B). This was not always the case for
interstitial cells. Apoptosis in
nonmyocytes was independent from the ventricular
hemodynamics, for example, EF (not shown), but it
correlated with the time of the disease (Figure 6C). These
correlations were done with the use of the data collected with the
Taq probe because of its specificity. However, similar
results were obtained when TdT values were used.
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Discussion |
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Cell Death in Acromegalic Heart
Findings in this investigation document that the increase in cardiac mass with acromegaly was characterized by structural abnormalities involving tissue fibrosis and ongoing myocyte and interstitial apoptotic cell death. Replacement fibrosis is the consequence of focal myocyte necrosis,18 19 whereas interstitial fibrosis may be independent from scattered cell necrosis and may result from the reaction of connective tissue cells to pathological loads.20 This is supported by the lack of evidence of acute myocyte necrosis, although difficulty exists in detecting this form of damage in the absence of specific markers. Apoptosis occurs without collagen accumulation in the ventricular wall, suggesting that the effects of this type of cell death do not involve changes in the volume composition of the myocardium. This is a well-established phenomenon in all organs.8 In 9 of the 10 cases analyzed here, there was thickening of the wall without a significant increase in cavitary diameter, indicating that concentric ventricular hypertrophy developed with acromegaly. Although defects in the compliance properties and shortening velocity occur with concentric hypertrophy,21 tissue scarring may alter muscle mechanical behavior.20 Similarly, myocyte apoptosis may impair the ability of the myocardium to develop force,10 decreasing pump function and EF. In the patient who had chamber dilation, relative wall thinning, and a 22% EF, myocyte death and collagen quantity were very high. In spite of these findings, it is not possible to establish whether chronic apoptotic cell death is the predominant event responsible for the deterioration of ventricular performance with acromegaly. However, it is likely that myocyte death, apoptotic and necrotic in nature, participates in the onset of ventricular dysfunction and its progression to cardiac failure. Cell death may account for the slow and partial recovery of contractility even after a successful removal of a GH-secreting pituitary adenoma.22
The 0.3% level of myocyte apoptosis detected here may question its role in ventricular dysfunction of acromegalic patients. In most cell types, this process is completed between 20 minutes and 2 hours,8 suggesting that the magnitude of cell death with time may be highly significant. In this regard, apoptosis in myocytes is responsible for mural slippage of cells and sudden changes in ventricular dimension.10 12 Ongoing cell loss negatively influences the anatomy and the hemodynamics of the heart; prevention of myocyte death in the surviving myocardium after infarction attenuates ventricular dilation, myocardial loading, and reactive hypertrophy.23 Comparable results have been obtained in hypertensive animals during the transition from compensated to decompensated myocardial hypertrophy.9 Lack of correlation between interstitial cell apoptosis and ventricular dysfunction is difficult to explain. Fibroblasts respond to apoptotic stimuli operative in myocytes, such as mechanical stretch,10 and this may be linked to the release of angiotensin II.11 However, fibroblasts are less susceptible to undergo apoptosis.10 Cell death in nonmyocytes may not represent a primary event of the cardiac myopathy with acromegaly, but this does not diminish the profound impact of collagen accumulation on myocardial performance.
IGF-1 and Cell Death in Acromegalic Heart
Several in vitro24 and in vivo23 studies
have demonstrated that IGF-1 interferes with apoptosis and
necrosis in various cell systems. Moreover, IGF-1 enhances cardiac
hypertrophy and limits ventricular remodeling,
improving myocardial function after infarction.25 Similar
results have been obtained in patients with dilated
cardiomyopathy.26 In both cases, the
favorable changes produced by IGF-1 may be the consequence of
attenuation of myocyte death in the heart. IGF-1 administration reduces
cell necrosis and apoptosis in ischemia-reperfusion
injury,27 and overexpression of IGF-1 in transgenic mice
prevents the activation of necrotic and apoptotic myocyte death
in the surviving myocardium after
infarction.23 On the basis of these observations, the
detection of apoptosis in myocytes and interstitial
cells in acromegaly was surprising. Several possibilities may be
advanced. IGF-1 induces myocytes to reenter the cell
cycle.28 29 This growth factor activates cyclins
and cyclin-dependent kinases in myocytes and cells enter the S-phase,
replicating DNA.29 In response to a sudden increase in
ventricular loading, the myocyte IGF-1–IGF-1 receptor
system is upregulated in vivo,30 and this adaptation is
coupled with enhanced induction and phosphorylation of
cyclins and cyclin-dependent kinases.31 Mice
overexpressing IGF-1 characteristically show cardiac
hypertrophy mediated by myocyte
proliferation.32 In the acromegalic heart, cell
regeneration may be accompanied by a certain degree of
apoptosis. Myocytes with DNA damage do not reenter the cell
cycle but may trigger their endogenous cell death pathway.
Such a condition has recently been documented
experimentally.33 Alternatively, IGF-1 reduced only in
part the stimulation of apoptosis in the decompensated
heart.5 6 Finally, chronic high levels of circulating
IGF-1 may have resulted in a downregulation of IGF-1 receptors on
cardiac muscle and nonmuscle cells.
Study Limitations
There are limitations that must be acknowledged. Control
myocardium from healthy human beings was not available.
Papillary muscles from patients with mitral stenosis are
inevitably exposed to some unloading that could have influenced the
collected results. Although 2 histochemical methods were used to
evaluate apoptosis, this phenomenon could not be confirmed by
DNA agarose gel electrophoresis. TdT reaction and Taq in
situ ligation provided essentially identical results, documenting that
the TdT assay with a fluorescent probe is a reliable technique
for the detection of apoptosis.11 Ongoing
myocyte necrosis could not be evaluated; this form of cell death may be
relevant in the progression of the cardiac disease. Finally, biopsies
are small in size and were collected at only 1 time point. All these
variables have to be considered in the interpretation of the
results obtained here.
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Acknowledgments |
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This work was supported by grants HL-38132, HL-39902, HL-43023, and AG-15756 from the National Institutes of Health. The 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 302, New York Medical College, Valhalla, NY 10595.
Received September 25, 1998; revision received November 16, 1998; accepted December 7, 1998.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. McGuffin WL, Sherman BM, Roth J, Gorden P, Kahn CR, Roberts WC, Frommer PL. Acromegaly and cardiovascular disorders: a prospective study. Ann Intern Med. 1974;81:11–18.
2. Fazio S, Cittadini A, Cuocolo A, Merola B, Sabatini D, Colao A, Biondi B, Lombardi G, Saccà L. Impaired cardiac performance is a distinct feature of uncomplicated acromegaly. J Clin Endocrinol Metab. 1994;79:441–446.[Abstract]
3. Lie JT, Grossman SJ. Pathology of the heart in acromegaly: anatomic findings in 27 autopsied patients. Am Heart J. 1980;100:41–52.[Medline] [Order article via Infotrieve]
4. Melmed S. Acromegaly. N Engl J Med.. 1990;322:966–977.[Medline] [Order article via Infotrieve]
5.
Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie
FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw B-A.
Apoptosis in myocytes in end-stage heart failure. N
Engl J Med. 1996;335:1182–1189.
6.
Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W,
Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewski S, Reed JC,
Anversa P. Apoptosis in the failing human heart. N
Engl J Med. 1997;336:1131–1141.
7. Darzynkiewicz Z, Juan G, Li X, Gorczyca W, Murakami T, Traganos F. Cytometry in cell necrobiology: analysis of apoptosis, accidental cell death and necrosis. Cytometry. 1997;27:1–20.[Medline] [Order article via Infotrieve]
8. Anversa P, Olivetti G, Leri A, Liu Y, Kajstura J. Myocyte cell death and ventricular remodeling. Curr Opin Nephrol Hypertens. 1997;6:169–176.[Medline] [Order article via Infotrieve]
9.
Li Z, Bing OHL, Long X, Robinson KG, Lakatta EG.
Increased cardiomyocyte apoptosis during the
transition from hypertrophy to heart failure in the
spontaneously hypertensive rats. Am J Physiol. 1997;272:H2313–H2319.
10. Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P. Stretch-induced programmed myocyte cell death. J Clin Invest. 1995;96:2247–2259.
11. Leri A, Claudio PP, Li Q, Wang X, Reiss K, Wang S, Malhotra A, Kajstura J, Anversa P. Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. J Clin Invest. 1998;101:1326–1342.[Medline] [Order article via Infotrieve]
12. Cheng W, Kajstura J, Nitahara JA, Li B, Reiss K, Liu Y, Clark WA, Krajewski S, Reed JC, Olivetti G, Anversa P. Programmed cell death contributes to ventricular remodeling after myocardial infarction in rats. Exp Cell Res. 1996;226:316–327.[Medline] [Order article via Infotrieve]
13. Anversa P, Olivetti G, Meggs LG, Sonnenblick EH, Capasso JM. Cardiac anatomy and ventricular loading after myocardial infarction. Circulation. 1993;87(suppl II):VII-22-VII-27.
14.
Devereux RB, Reichek N.
Echocardiographic determination of left
ventricular mass in man: anatomic validation of the method.
Circulation. 1977;55:613–618.
15.
Didenko VV, Hornsby PJ. Presence of double-stranded
breaks with single-base 3' overhangs in cells undergoing
apoptosis but not necrosis. J Cell Biol. 1996;135:1369–1376.
16. Snedecor GW, Cochran WG. Statistical Methods. 7th ed. Ames, Iowa: Iowa State University Press; 1980:130–134.
17. Merimee TJ, Quinn S, Russell B, Riley W. The growth hormone-insulin-like growth factor I axis: studies in man during growth. In: Raizada MK, LeRoith D, eds. Molecular Biology and Physiology of Insulin and Insulin-Like Growth Factors. New York, NY: Plenum Press; 1991:85–96.
18.
Benjamin IJ, Jalil E, Tan LB, Cho K, Weber KT, Clark
WA. Isoproterenol-induced myocardial fibrosis in relation to myocyte
necrosis. Circ Res. 1989;65:657–670.
19. Buja LM, Willerson JT. The role of coronary artery lesions in ischemic heart disease: insight from recent clinicopathologic, coronary arteriographic, and experimental studies. Hum Pathol. 1987;18:451–461.[Medline] [Order article via Infotrieve]
20.
Weber KT, Brilla CG. Pathological
hypertrophy and cardiac interstitium: fibrosis and
renin-angiotensin-aldosterone system.
Circulation. 1991;83:1849–1865.
21. Lakatta EG. Length modulation of muscle performance: Frank-Starling law of the heart. In: Haber E, Jennings RB, Katz AM, Morgan HE, eds. The Heart and Cardiovascular System. New York, NY: Raven Press; 1986:319–843.
22. Nieminen MS, Elonen E, Pelkonen R, Frick MH. Acromegaly and the heart. Circulation. 1978;58:757.[Medline] [Order article via Infotrieve]
23. Li Q, Li B, Wang X, Leri A, Jana KP, Liu Y, Kajstura J, Baserga R, Anversa P. Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J Clin Invest. 1997;100:1991–1999.[Medline] [Order article via Infotrieve]
24.
Resnicoff M, Burgaud J-L, Rotman HL, Abraham D, Baserga
R. Correlation between apoptosis, tumorigenesis, and levels of
insulin-like growth factor 1 receptors. Cancer Res. 1995;55:3739–3741.
25. Duerr R, Huang S, Miraliakbar HR, Clark RG, Chien K, Ross J Jr. Insulin-like growth factor I enhances ventricular hypertrophy and function during the onset of experimental cardiac failure. J Clin Invest. 1995;95:619–627.
26.
Fazio S, Sabatini D, Capaldo B, Vigorito C, Giordano A,
Guida R, Pardo F, Biondi B, Saccà L. A preliminary study of
growth hormone in the treatment of dilated
cardiomyopathy. N Engl J Med. 1996;334:809–814.
27.
Buerke M, Murohara T, Skurk C, Nuss C, Tomaselli K,
Lefer AM. Cardioprotective effect of insulin-like growth factor 1 in
myocardial ischemia followed by reperfusion. Proc Natl
Acad Sci U S A. 1995;92:8031–8035.
28.
Decker RS, Cook MG, Behnke-Barclay M, Decker ML. Some
growth factors stimulate cultured adult rabbit ventricular
myocyte hypertrophy in the absence of mechanical loading.
Circ Res. 1995;77:544–555.
29. Reiss K, Cheng W, Pierzchalski P, Kodali S, Li B, Wang S, Liu Y, Anversa P. Insulin-like growth factor-1 receptor and its ligand regulate the reentry of adult ventricular myocytes into the cell cycle. Exp Cell Res. 1997;235:198–209.[Medline] [Order article via Infotrieve]
30.
Cheng W, Reiss K, Li P, Chun MJ, Kajstura J, Olivetti
G, Anversa P. Aging does not affect the activation of the myocyte
insulin-like growth factor-1 autocrine system after infarction and
ventricular failure in Fischer 344 rats. Circ
Res. 1996;78:536–546.
31. Reiss K, Cheng W, Giordano A, De Luca A, Li B, Kajstura J, Anversa P. Myocardial infarction is coupled with the activation of cyclins and cyclin-dependent kinases in myocytes. Exp Cell Res. 1996;225:44–54.
32.
Reiss K, Cheng W, Ferber A, Kajstura J, Li P, Li B,
Olivetti G, Homcy CJ, Baserga R, Anversa P. Overexpression of
insulin-like growth factor-1 in the heart is coupled with myocyte
proliferation in transgenic mice. Proc Natl Acad Sci
U S A. 1996;93:8630–8635.
33. Agah R, Kirshenbaum LA, Abdellatif M, Truong LD, Chakraborty S, Michael LH, Schneider MD. Adenoviral delivery of E2F-1 directs cell cycle reentry and p53-independent apoptosis in postmitotic adult myocardium in vivo. J Clin Invest. 1997;100:2722–2728.[Medline] [Order article via Infotrieve]
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