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(Circulation. 2000;101:2863.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Cardiac Hypertrophy Is Not a Required Compensatory Response to Short-Term Pressure Overload
From the Division of Cardiovascular Diseases, Department of Internal Medicine (J.A.H., W.K., Z.W., R.E.K., R.M.W.), Department of Pharmacology (J.A.H.), Department of Veterans Affairs (J.A.H., K.Z., R.M.W.), Department of Surgery (M.K.), and Department of Anatomy and Cell Biology (R.L.D.), University of Iowa College of Medicine, Iowa City.
Correspondence to Joseph A. Hill, MD, PhD, Cardiovascular Division, University of Iowa College of Medicine, E318GH, UIHC, 200 Hawkins Dr, Iowa City, IA 52242-1081. E-mail joseph-hill{at}uiowa.edu
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Abstract |
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Background—Cardiac hypertrophy is considered a necessary compensatory response to sustained elevations of left ventricular (LV) wall stress.
Methods and Results—To test this, we inhibited calcineurin with cyclosporine (CsA) in the setting of surgically induced pressure overload in mice and examined in vivo parameters of ventricular volume and function using echocardiography. Normalized heart mass increased 45% by 5 weeks after thoracic aortic banding (TAB; heart weight/body weight, 8.3±0.9 mg/g [mean±SEM] versus 5.7±0.1 mg/g unbanded, P<0.05). Similar increases were documented in the cell-surface area of isolated LV myocytes. In mice subjected to TAB+CsA treatment, we observed complete inhibition of hypertrophy (heart weight/body weight, 5.2±0.3 mg/g at 5 weeks) and myocyte surface area (endocardial and epicardial fractions). The mice tolerated abolition of hypertrophy with no signs of cardiovascular compromise, and 5-week mortality was not different from that of banded mice injected with vehicle (TAB+Veh). Despite abolition of hypertrophy by CsA (LV mass by echo, 83±5 mg versus 83±2 mg unbanded), chamber size (end-diastolic volume, 33±6 µL versus 37±1 µL unbanded), and systolic ejection performance (ejection fraction, 97±2% versus 97±1% unbanded) were normal. LV mass differed significantly in TAB+Veh animals (103±5 mg, P<0.05), but chamber volume (end-diastolic volume, 44±6 µL), ejection fraction (92±2%), and transstenotic pressure gradients (70±14 mm Hg in TAB+Veh versus 77±11 mm Hg in TAB+CsA) were not different.
Conclusions—In this experimental setting, calcineurin blockade with CsA prevented LV hypertrophy due to pressure overload. TAB mice treated with CsA maintain normal LV size and systolic function.
Key Words: hypertrophy • cyclosporine • calcineurin
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Cardiac hypertrophy is a homeostatic response to elevated afterload that develops in response to pressure or volume overload, loss of contractile mass (prior infarction), or mutations of contractile (and other) proteins. This tenet is based on the long-held principle that ventricular geometry and wall thickness change to maintain systolic stress within normal limits.1 Although hypertrophy is thought to compensate for hemodynamic stress, echocardiographically documented myocardial hypertrophy is an independent risk factor for cardiovascular morbidity and mortality.2 Because hypertrophy imparts coincident risk of heart failure and sudden death stemming from malignant ventricular arrhythmias, the distinction between "compensatory" and pathological hypertrophy is uncertain.
A number of stimuli are known to induce cardiomyocyte
hypertrophy in vitro. These primary stimuli, which include
hormones, cytokines, growth factors, vasoactive peptides, and
catecholamines, trigger intricate reaction cascades with
multiple interacting branching points.3 4 Studies in vivo
using a physiologically relevant stimulus
(pressure overload) have identified 4 means of preventing cardiac
hypertrophy apart from lowering blood pressure: inhibition
of ACE,5 G
q,6
calcineurin,7 8 9 or c-Jun
NH2-terminal kinase.10
Calcineurin participates in hypertrophic signal transduction in models of cardiac7 9 11 and skeletal muscle12 13 14 biomechanical stress. In this study, we used cyclosporine (CsA), a specific inhibitor of calcineurin,15 16 as a tool to examine morphological and functional effects of pressure overload on the heart in the presence and absence of left ventricular hypertrophy (LVH). We tested the classic hypothesis that hypertrophy is a necessary compensatory mechanism for pressure overload by analyzing myocardial function in vivo by echocardiography.
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Methods |
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Thoracic Aortic Banding
Increased pressure in the proximal aorta was induced by means of thoracic aortic banding17 (TAB) (Figure 1A
) according to protocols approved by
the institution’s Animal Care and Use Committee. Male mice (C57Bl6, 6
to 8 weeks old) were anesthetized with ketamine (100
mg/kg IP) plus xylazine (5 mg/kg IP). The mice were orally intubated
with 20-gauge tubing and ventilated (Harvard Apparatus
Rodent Ventilator, model 687) at 120 breaths per minute (0.1-mL tidal
volume). A 3-mm left-sided thoracotomy was created at the second
intercostal space. The transverse aortic arch was ligated (7-0 Prolene)
between the innominate and left common carotid arteries with an
overlying 27-gauge needle, and then the needle was removed, leaving a
discrete region of stenosis. The chest was closed, and the
left-sided pneumothorax was evacuated. Some mice were subjected to a
sham operation in which the aortic arch was visualized but not banded.
Perioperative (24 hours) and 1-week mortalities were
each <10%.
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On the morning of postoperative day 1, banded and sham-operated mice were randomized to receive either CsA 25 mg/kg SC twice daily or an equal volume of vehicle SC twice daily. Postmortem blood samples were collected, and CsA trough levels were 2.6±0.2 µg/mL (n=11), a level 150-fold higher than the IC50 for calcineurin inhibition in mice (18 µg/L)18 and higher than that reported to inhibit 90% of total calcineurin phosphatase activity in the heart.7 19 20
Hemodynamics and Morphology
In 11 mice anesthetized with ketamine (90 mg/kg
IP) and acepromazine (1.8 mg/kg IP), the right and left carotid
arteries were exposed and cannulated with fine catheters pulled from
Microrenathane tubing. Blood pressure was recorded
simultaneously in both carotid arteries.
After the study period, the heart was removed from heparinized (500 U)
mice euthanized with a lethal dose of pentobarbital (150 mg/kg). The
heart and 1 cm of aorta (including the stenotic segment) were
rapidly excised. The banding ligature was removed, and the heart was
blotted dry and weighed. Data are reported as heart mass (rather than
LV mass) to allow for retrograde-perfusion enzymatic dissociation of
myocytes.21 The surface area of a 2D silhouette of the
myocyte was estimated by measurement of the length and width of 10
randomly selected myocytes from endocardium-enriched and
epicardium-enriched fractions. Our reported 2D surface area
(lengthxwidth) is directly proportional to the surface area of a
cylinder (2
xradiusxlength).
Echocardiography
Conscious sedation was achieved with midazolam 0.2 to 0.3 mg SC.
The anterior chest was shaved, and prewarmed ultrasonic gel was
applied. Views were taken in planes that approximated the parasternal
short-axis view (chordal level) and the apical long-axis view in
humans. The apex was visualized in all mice. Transthoracic
echocardiograms were recorded with a 13-MHz probe on a Sequoia 256
Acuson echocardiograph at a frame rate of 162 frames
per second.
Diastole, designated as the time when LV volume was greatest, was identified in both short- and long-axis projections. In the short-axis view, the endocardial and epicardial silhouettes were manually traced by use of the "leading edge–to–leading edge" convention. The papillary muscles were not visualized in the chordal level short-axis views we obtained. In the long-axis projection, LV length was measured for both endocardial and epicardial surfaces by measuring from each respective location at the cardiac apex to the center of the mitral valve plane. LV mass and volumes were calculated by the area-length method.22 Heart rate was determined by measuring cycle length of pulse-wave Doppler interrogation of mitral inflow.
We examined the validity of our 2D echocardiographic image acquisition and ventriculographic measurements in a separate group of 6 mice (2 to 6 months old). After echocardiographic examination, the animals were euthanized, and left ventricles were dissected, blotted dry, and weighed.
Statistical Methods
Data are reported as mean±SEM. Statistical significance was
analyzed by Student’s unpaired t test or 1-way
ANOVA followed by Bonferroni’s method for post hoc pairwise multiple
comparisons. Statistical significance was defined as a value of
P<0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Cardiac Hypertrophy in Pressure-Overload Mice
TAB produced a large pressure gradient between the left and right carotid arteries (Figure 1B
; peak systolic gradient,
70±14 mm Hg; n=6). Measurements at different times after surgery
(n=11, 4 hours to 5 weeks) revealed no significant change in pressure
gradients over time.
During the 5 weeks after banding, heart mass increased 66%, from
135±3 to 224±28 mg (P<0.05). The mice grew and gained
weight during the course of the study, and as a control, we measured
heart mass as a function of body mass (HW/BW). HW/BW increased from
5.7±0.1 to 8.3±0.9 mg/g (45% increase, P<0.05) (Figure 1C). Other methods of controlling for the size of the mouse gave
similar results. Heart weight normalized to tibia length (HW/T)
increased 62%, from 8.0±0.2 to 13.0±0.7 mg/mm, P<0.05)
(Figure 1D). Normalized heart mass did not increase
significantly in sham-operated mice killed at 5 weeks (HW/BW,
5.57±0.01; HW/T, 8.0±0.14; n=20; Figures 1C and 1D).
Total heart length (base to apex) normalized to tibia length increased from 0.46±0.01 to 0.55±0.02 mm/mm (P<0.05). Heart width measured at the level of the AV groove and normalized to tibia length increased from 0.325±0.007 to 0.40±0.02 mm/mm (P<0.05). ECG in alert, unrestrained mice revealed resting heart rates that were similar (655±39 bpm, n=3) to those of control mice (668±30 bpm, n=10).
Increases in heart size and mass may be the result of changes in either
myocyte or nonmyocyte fractions of myocardium. To
investigate this, individual ventricular myocytes were
enzymatically dissociated and examined microscopically (Figure 2A). Myocyte 2D surface area (myocyte
lengthxwidth) was similar in endocardial and epicardial fractions and
in unoperated and sham-operated mice (Figure 2B). In contrast,
2D surface area increased in myocytes isolated from hearts subjected to
TAB (Figure 2B). Cardiomyocyte enlargement was proportional to
normalized heart mass in endocardial and epicardial cell fractions
(Figure 2C). Histological examination of the
hypertrophied myocardium did not reveal evidence of
significant tissue fibrosis or myofibrillar disarray (data not
shown).
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Effects of CsA
Mice injected with CsA (TAB+CsA) and vehicle (TAB+Veh) tolerated
mechanical loading equally well, with no detectable clinical
differences (lethargy, tachypnea, impaired mobility, edema). Body mass
continued to increase normally (Figure 3C), and the mice did not exhibit signs
of cardiovascular compromise (effusions, ascites,
hepatic congestion). One-week and 5-week mortality were each <10% in
both groups.
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, same
as in Figure 1C
). Number of hearts
analyzed is indicated beside each data point. B, Short-axis
sections at level of papillary muscles from hearts subjected to TAB or
TAB+CsA vs age-matched unoperated control. C, Body mass plotted as a
function of age in unoperated control mice and in mice subjected to
TAB+Veh or TAB+CsA.
CsA blocked the development of hypertrophy, as measured by
HW/BW (Figure 3A) or HW/T (data not shown). At every time point
up to 5 weeks, HW/BW and HW/T in TAB+CsA animals did not differ
significantly from control. In contrast, there was a significant
increase in heart mass in TAB+Veh mice from 1 to 5 weeks after banding
(Figure 3A). Similarly, heart dimensions were not significantly
different in TAB+CsA mice compared with controls, whereas these values
increased significantly in TAB+Veh mice after banding (data not
shown).
Short-axis sections through the heart at the level of the papillary
muscles (Figure 3B) revealed thickening of the LV wall in the
TAB+Veh hearts, whereas hearts from TAB+CsA mice were indistinguishable
from hearts from control mice. Hearts from TAB+CsA mice were similar in
appearance to hearts from age-matched unoperated mice.
The 2D surface area of myocytes isolated from TAB+CsA mice did not
differ significantly from that of myocytes isolated from unoperated
animals but was significantly greater in cells isolated from TAB+Veh
mice (Figure 4A). The surface area of
myocytes subjected to TAB+CsA was proportional to normalized heart mass
(Figure 4B) and was well described by regression lines derived
from the TAB+Veh hearts (Figure 2C), even though no hearts
larger than HW/T=9 were ever observed.
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) plotted as a function
of normalized heart mass (HW/T) with regression lines derived from
TAB+Veh hearts superimposed (Figure 2CCsA had no effect on the transstenotic aortic pressure gradient. Systolic gradients measured in 5 mice subjected to TAB+CsA for 2 to 5 weeks were 77±11 mm Hg, which was not significantly different from the gradients measured in TAB+Veh animals (70±14 mm Hg, n=6).
In Vivo Function
To test the hypothesis that hypertrophy is an
obligatory adaptive response, we studied in vivo cardiac function by
transthoracic echocardiography (Figure
I; this figure can be found online at
http://www.circulationaha.org).
Echocardiographic measurements provided a reliable
estimate of LV mass (Figure 5A). These
findings document the fidelity of endocardial and epicardial edge
identification and support the validity of measurements of LV cavity
volume. Under these recording conditions, there were no
significant differences in heart rate (TAB+Veh, 645±28 bpm; TAB+CsA,
656±16 bpm; control, 626±16 bpm), and these values do not differ from
those measured electrocardiographically in the absence of sedation (see
above).
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2D echocardiography was performed to evaluate
systolic function and chamber size (Figures 5B and 5C)
in animals subjected to TAB+Veh (n=6) versus TAB+CsA (n=7). As expected
from postmortem data, LV mass by echocardiography
at 3 weeks was significantly greater in mice subjected to TAB+Veh
(103±4 mg, n=6) than in animals subjected to TAB+CsA (83±4 mg, n=3,
P<0.05). LV mass in TAB+ CsA mice was not significantly
different from that of age-matched control values (83±2 mg, n=7).
End-diastolic volumes were not significantly different in all 3 groups at 3 weeks (TAB+Veh, 44±6 µL; TAB+CsA, 33±6 µL; control, 37±1 µL), indicating the absence of chamber dilation. Similarly, ejection fractions (TAB+Veh, 92±2%; TAB+CsA, 97±2%; control, 97±1%) and cardiac output (TAB+Veh, 24±4 mL/min; TAB+CsA, 21±3 mL/min; control, 23±3 mL/min) were not significantly different. Studies in TAB+CsA mice (n=4) at 1 to 2 weeks revealed similar evidence of preserved LV chamber size and systolic function (LV mass, 73±5 mg; end-diastolic volume, 31±7 µL; ejection fraction, 99±1%). In only 1 of 25 mice imaged at 4 weeks after surgery was systolic dysfunction observed, and this mouse (LV mass, 148 mg; end-diastolic volume, 107 µL; end-systolic volume, 46 µL; ejection fraction, 57%) had been exposed to TAB+Veh treatment.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The most important finding of this study is that abolition of the hypertrophic response to systolic pressure overload does not result in LV decompensation. This finding is supported by 6 independent lines of evidence. First, there was no clinical or actuarial evidence of heart failure in CsA-treated mice. Second, postmortem gross anatomy demonstrated no signs of cardiac dilatation or evidence of heart failure (eg, effusions, ascites, edema). Third, postmortem cardiac histopathology revealed an absence of myocardial fibrosis or other evidence of myocyte damage. Fourth, examination of single myocytes revealed normal cell size and microscopic appearance. Fifth, pressure gradients measured across the surgically induced stenosis were similar in the presence and absence of hypertrophy. Sixth, echocardiography consistently demonstrated maintenance of normal systolic function in CsA-treated mice.
Structural Consequences of Calcineurin Inhibition
The efficacy of CsA abolition of the hypertrophic response in our
model is verified by 3 independent methods. First, gross pathology
indicated no difference with respect to heart mass in banded mice
treated with CsA compared with unbanded mice. By examining multiple
time points during development of hypertrophy, we found
that statistically significant differences appear as early as 1 week,
the earliest time point examined. The curves continue to diverge at
least as late as 5 weeks after banding. Second, the dimensions of
myocytes isolated from banded mice treated with CsA were similar to
those in unbanded mice. Third, in vivo
echocardiography demonstrated that LV mass in
banded mice treated with CsA was similar to that obtained from unbanded
controls.
This is the first report of abolition of pressure-overload hypertrophy by calcineurin blockade in mice exposed to pressure overload. CsA blocked hypertrophy in all 34 mice studied, including 4 mice studied at 5 weeks. There was no evidence of nonspecific toxicity, because we observed no effects on normal growth, weight gain, or physical activity (similar to observations by others).8 12 20
Calcineurin inhibition does not prevent hypertrophy in all models of pressure overload. To date, 6 complete reports (including this work) and 2 letters have been published pertaining to the effects of calcineurin inhibition on pressure-overload hypertrophy: 3 groups report profound inhibition of hypertrophy (this work and References 7 and 9 ), 3 report no effect,20 23 24 and 2 detect an intermediate response.8 19 The 3 positive studies have been in different species (Sprague-Dawley7 and Wistar9 rats and C57Bl6 mice [this report]) subjected to different operations (suprarenal aortic banding7 9 and TAB [this report]).
Reasons for the contradictory findings are unclear. Technical differences among published reports are significant in terms of species, strain, age, surgical procedure, and the timing, dosage, and route of administration of CsA. Some groups have reported elevated mortality in mice treated with CsA,7 8 19 23 and it is possible that selecting CsA-treatment survivors may favor animals with relatively greater heart size. Surgical technique is also important25 ; for example, suprarenal aortic banding is associated with elevated plasma renin activity, unlike banding of the ascending aorta.26 Nuclear factor of activated T cells (NFAT) translocation to the nucleus is transient,13 and timing of the initiation of calcineurin inhibition may be crucial.
Zhang et al19 report LV mass normalized to body weight and pressure gradient (LVW/BW/gradient), arguing that this latter factor accounts for the potential influence of a smaller stimulus to hypertrophy. In our study, simultaneous carotid pressure measurements in anesthetized mice revealed similar transstenotic pressure gradients in TAB+Veh and TAB+CsA mice. This finding was extended to conscious, sedated mice in that we measured similar cardiac outputs in TAB+Veh and TAB+CsA mice, indicating that the pressure gradients (which vary as the square of cardiac output in the presence of a fixed stenosis) were similar. Ding et al20 report a 72% decrease in LV calcineurin activity in hypertrophied hearts; given this, one would not expect a significant impact from further calcineurin inhibition using CsA.
Functional Consequences of Calcineurin Inhibition
Compensatory hypertrophy putatively develops to
facilitate ejection performance of the overloaded ventricle by
normalizing systolic and diastolic wall stress. We
tested this idea by imposing a condition of elevated afterload while
blocking the compensatory response. As expected, mice subjected to
TAB+Veh exhibited significantly increased LV mass, and measures of
systolic performance were preserved. On the basis of
Laplace’s law, we predict that ventricular wall stress is
elevated in TAB+CsA mice (elevated systolic pressure without a
change in ventricular radius or wall thickness). If
hypertrophy were a necessary compensatory response, we
might predict that TAB+CsA mice would develop LV systolic
dysfunction, chamber dilatation, and myocyte lengthening. Our results
indicate that none of these occurred. Similarly preserved
systolic function in the setting of pressure overload but
without hypertrophic compensation was recently reported by 2 other
groups.9 10
Maintenance of cardiac output in the face of increased afterload but without change in end-diastolic or end-systolic volumes implies a positive inotropic effect. Homeometric autoregulation (Anrep effect) was first described in 191227 28 and has been reported in a variety of working heart models.25 29 30 31 32 Our findings are consistent with a sustained Anrep effect. Additional work will be necessary to test this hypothesis.
None of the animals in this study developed heart failure. Meguro et
al8 reported a 7-fold increased risk of death from heart
failure (defined as presence of pleural effusion and increased lung
weight) after banding in mice treated with CsA, and most of this excess
mortality appeared to occur in the first 2 to 3 days after surgery.
This is somewhat surprising, because these investigators reported only
a modest decrease in ejection fraction (
78% in TAB versus 66% in
TAB+CsA, data taken from their Figure 2), and LV volumes were not
reported. These investigators also reported an all-cause 10-day
mortality of 43% in TAB mice and 72% in TAB+CsA mice, which is
markedly higher than ours (<10% in each group), suggesting
significant differences in perioperative milieu.
Our echocardiographic measurements were performed under
conditions of conscious sedation so as to maintain
physiological heart rates, ventilation, and
inotropic state. We observe cavity near-obliteration at end
systole (Figure I), accounting for ejection fractions 90%. These
values may be artifactually inflated; although LV short- and long-axis
silhouettes were consistently visualized, the area-length
method does not account for residual blood pooled beneath the mitral
and aortic valves. Nevertheless, the physiological
conclusions derived from these measurements are valid.
Ejection-phase indices of murine LV function in studies that used general anesthesia are generally lower than in our study. General anesthetics directly depress myocardial contractility, and positive-pressure ventilation is known to perturb cardiac function. Furthermore, the adequacy of systemic oxygenation and acid-base balance during general anesthesia is difficult to assess in mice and is seldom reported. Yang et al33 performed echocardiography in conscious, sedated, minimally restrained mice, and they report ejection fractions similar to those in our study. Thus, it appears that normal conscious mice have significantly higher ejection fractions than anesthetized mice.
Perspective
Even though calcineurin is activated in heart failure in
humans,34 envisioning use of CsA as treatment for
hypertrophy or heart failure is
problematic.35 36 Nevertheless, our data
support the hypothesis that activation of a calcineurin transcriptional
pathway mediates at least an early component of pressure-overload
hypertrophy. Furthermore, the major implication of the
findings is that hypertrophy is not a necessary adaptive
response to elevated cardiac workload in this model.
Note Added in Proof
Bartunek et al37 have shown that rats rendered
hypertensive by L-NAME infusion (an inhibitor of nitric oxide synthase
that also suppresses protein synthesis) maintain left ventricular
systolic performance despite the absence of hypertrophic compensation.
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Acknowledgments |
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This work was supported by grants from the Roy J. Carver Charitable Trust, the Department of Veterans Affairs, and the AHA, Heartland Affiliate (all to Dr Hill), and the AHA (Dr Weiss). We gratefully acknowledge Drs Curt Sigmund and Linda Cadaret for support during the early echocardiography experiments and Milan Sonka for assistance with the digitized echocardiograms. We sincerely thank Drs Donald Heistad, Michael Welsh, and Kevin Campbell for helpful advice and encouragement.
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Footnotes |
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This article has an Online-only Figure
, which can be found at http://www.circulationaha.org Received October 25, 1999; revision received December 29, 1999; accepted January 31, 2000.
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