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Cardiology Unit, Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont 05401
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The effect of protein
kinase C (PKC) activation on cardiac mechanoenergetics is not fully
understood. To address this issue, we determined the effects of the PKC
activator phorbol 12-myristate 13-acetate (PMA) on isolated rat hearts.
Hearts were exposed to PMA with or without pretreatment with the PKC
inhibitor chelerythrine. Contractile efficiency was assessed as the
reciprocal of the slope of the linear myocardial O2
consumption (
O2) pressure-volume area
(PVA) relation. PMA decreased contractility
(Emax; 
30 ± 8%; P < 0.05) and increased coronary perfusion pressure (+58 ± 11%;
P < 0.01) without altering left ventricular
end-diastolic pressure. Concomitantly, PMA decreased PVA-independent
O2 [nonmechanical energy expenditure
for excitation-contraction (E-C) coupling and basal metabolism] by
28 ± 8% (P < 0.05) and markedly increased contractile efficiency (+41 ± 8%; P < 0.05) in
a manner independent of the coronary vascular resistance. Basal
metabolism was not affected by PMA. Chelerythrine abolished the
PMA-induced vasoconstriction, negative inotropy, decreased
PVA-independent O2, and increased contractile efficiency. We conclude that PKC-mediated phosphorylation of regulatory proteins reduces O2 via
effects on both the contractile machinery and the E-C coupling.
mechanoenergetics; protein kinase C; excitation-contraction coupling; inotropy; phorbol ester
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ACTIVATION OF PROTEIN KINASE C (PKC) has been shown to modulate the function of several regulatory proteins (17, 24, 27, 33). PKC-mediated phosphorylation of the thin-filament proteins troponin I and T results in decreased myofibrillar ATPase activity (33). This suggests that PKC activity influences the chemomechanical conversion efficiency of the contractile machinery. However, whether this results in physiologically meaningful mechanoenergetic effects in vivo is unknown. This question may also be relevant to failing myocardium, which manifests decreased myofibrillar ATPase activity, increased contractile efficiency and economy, and alterations in thin-filament regulatory protein phosphorylation (18). Moreover, recent evidence suggests that increased PKC activity plays an important role in heart failure (3, 13, 34).
To clarify the role of PKC activation in the normal rat heart, we
delineated the mechanoenergetic effects of the PKC activator phorbol
12-myristate 13-acetate (PMA) on left ventricular (LV) mechanoenergetics in isolated crystalloid-perfused rat hearts by
employing the myocardial O2 consumption
(O2) pressure-volume area (PVA)
framework. The linear relationship between
O2 and PVA provides information about
the chemomechanical conversion efficiency of the contractile machinery
(the contractile efficiency) as well as quantification of energy use
for excitation-contraction (E-C) coupling and basal metabolism
(11, 31). We selected a dose of PMA that produced a
substantial decrease in contractile function that is comparable to the
decrease observed clinically in failing hearts. We show that activation
of PKC reduces O2 by effects on both the
contractile machinery and E-C coupling.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All experiments were performed with the approval of the University of Vermont Animal Research Committee.
Isolated heart preparation. The preparation used in this study has been described elsewhere (18). In brief, hearts isolated from male Sprague-Dawley rats weighing 350-400 g (n = 36) were perfused by the Langendorff method with Krebs-Henseleit buffer consisting of (in mM) 108.8 NaCl, 4.0 KCl, 1.4 MgSO4, 1.4 KH2PO4, 25.0 NaHCO3, 11.0 dextrose, 10.0 sodium pyruvate, and 2.0 CaCl2 (18). The perfusate was filtered, equilibrated with 95% O2-5% CO2, warmed to 37°C, and adjusted to pH 7.4 by changing the CO2 concentration. Coronary flow was initially adjusted to provide a mean coronary perfusion pressure (CPP) of 90 mmHg. Flow was kept constant thereafter by using a Masterflex peristaltic pump while CPP was allowed to vary. A thin high-density polyethylene balloon mounted on a Y connector was placed in the LV cavity through the mitral orifice (18). A 2.5-Fr micromanometer (Millar Instruments) was inserted through the center of the balloon via a side port. A pacing electrode was attached to the left ventricle and connected to a stimulator (Grass Instruments). The left ventricle was subsequently paced at 240 beats/min and contracted isovolumically (18).
Myocardial O2 measurement.
The coronary arteriovenous O2 content difference (AVOD) was
measured using an Instech O2 monitor (Instech Laboratories;
Plymouth, PA). LV pressure, CPP, and AVOD values were stored on a hard
disk at 2-ms sampling intervals for off-line analyses.
O2 per minute was calculated as coronary
flow (ml/min) × AVOD (vol %) 
heart rate (beats/min) and
normalized per gram of left ventricle to yield the total
O2 per beat per gram (in milliliters).
LV volume was determined as the volume of water within the balloon plus the volume of the balloon walls and the connector within the left ventricle. LV developed pressure was the difference between the peak
and minimum pressures. End-diastolic pressure (EDP) was measured when
the first derivative of LV pressure with respect to time (dP/dt) reached 10% of maximum. The coronary effluent was
time-collected to measure the coronary flow rate and to determine the
myocardial lactate production.
Experimental protocol.
The first series of experiments was designed to establish the
PKC-selective actions of PMA. The effects of three treatments administered via the coronary perfusate were tested: 1) 10 nM PMA (n = 13), 2) 2 µM chelerythrine (a
PKC inhibitor; n = 7), and 3) 10 nM PMA + 2 µM chelerythrine (n = 7). The hearts were allowed
to stabilize for 20 min before each protocol. After stabilization, the
hearts were exposed to the agents for 30 min. The infusion was then
terminated, and the hearts were monitored for 30 min of recovery.
Treatment with chelerythrine was initiated 15 min before PMA infusion
and was continued throughout the remainder of the experiment.
Measurement of LV pressure, CPP, coronary flow, and AVOD were made at
various balloon volumes (the volume run) during steady-state isovolumic
contractions. After the volume run was completed under control
conditions, the three different treatment agents were added to the
coronary perfusate. The volume run was then repeated (under
steady-state conditions) 30 min after the infusion was started. To
compare the possible effects of each agent on basal metabolism, four
hearts in each group were arrested at zero balloon volume after the
first volume run by injection of intracoronary KCl. When both coronary
flow and AVOD were stabilized, basal metabolic
O2 was measured over a 1-min time
period. After control basal metabolism was measured, hearts were
recovered by reinstituting the normal perfusate, and each treatment was
then added to the coronary perfusate. At the end of the study, these hearts were rearrested by injection of KCl for measurement of the basal
metabolism after drug intervention. Because we found that PMA caused a
major increase in coronary vascular resistance that required us to
increase the CPP to maintain constant coronary flow, we used the same
protocols in a separate series of experiments to determine the
independent mechanoenergetic effects of 30 min of increased CPP (160 mmHg; n = 5) or inhibition of nitric oxide (NO)
synthesis with 100 µM
N
-nitro-L-arginine
(L-NNA; n = 4). The latter treatment was
designed to increase coronary vascular resistance via a
non-PKC-mediated mechanism.
Data analysis.
For each volume run, the LVEDP and peak-systolic pressure were plotted
against the LV volume to construct the pressure-volume diagram. To
assess the contractile state of the left ventricle, the end-systolic
pressure-volume relation (ESPVR) was fitted to a nonlinear regression
analysis (4, 12, 18)
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is a constant.
The total energy liberated by the ventricle under isovolumic conditions
was quantified as the PVA, the area circumscribed by the ESPVR, the
end-diastolic pressure-volume relation (EDPVR), and the systolic
portion of the pressure-volume trajectory (31). The value
of the PVA was normalized per gram of LV mass (in
mmHg · ml · beats
1 · g1).
O2 was plotted as a function of PVA as
LV volume was varied, and a linear regression analysis
(O2 = aPVA + b) was performed; slope a represents the
O2 cost of PVA, and intercept b shows the O2 at PVA = 0 (for unloaded or
PVA-independent O2 values). PVA-independent O2 consists of
nonmechanical energy expenditure for E-C coupling and basal metabolism
(31). The slope (a1) is the
efficiency of the conversion of O2 to
PVA (the contractile efficiency) after conversion of PVA and
O2 to joules (4). LV
O2 during KCl arrest was expressed as
milliliters of O2 × milliliters × minutes1 × grams1. Because unloaded
O2 is mainly used for E-C coupling and
basal metabolism, O2 for E-C coupling
(measured in ml
O2 · beats1 · g1)
was estimated as unloaded O2 per
minute O2 for basal metabolism per minute heart rate.
Chemicals.
PMA, DMSO, L-NNA, and chelerythrine were obtained from
Sigma Chemical (St. Louis, MO). A stock solution of PMA (1 mM PMA in DMSO, frozen at 20°C) was diluted in phosphate-buffered saline before infusion. We confirmed in a preliminary study that the DMSO
solution alone did not affect CPP or myocardial contraction. PMA was
infused into the perfusion line 2-3 cm above the aortic valve with
a Harvard infusion pump to deliver the desired concentrations. The
syringe/infusion line was wrapped in foil to protect this agent from light.
Statistical analysis.
Data are expressed as means ± SD. Differences in mechanical and
hemodynamic parameters between the control and the experimental drug-intervention conditions were detected by Student's
t-test. Differences in the
O2-PVA regression lines between the two
conditions were detected by analysis of covariance. Comparisons of
variables among the groups were made by one-way ANOVA. A value of
P < 0.05 was taken to indicate significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of PMA on ESPVR and O2-PVA
relationship.
After initiation of the PMA infusion, LV developed pressure
progressively decreased for ~20 min before a new steady state was
reached. Figure 1A shows the
effect of PMA on LV pressure-volume relations 30 min after the infusion
was begun in a representative heart. PMA shifted the ESPVR downward;
however, there was no significant change in the EDPVR. As summarized in
Fig. 1B, PMA decreased Emax by an
average of 30% (P < 0.05). Figure
2A shows the
O2-PVA relation before and after PMA
perfusion in a representative heart. O2
was linearly and tightly correlated with the corresponding PVA in each
condition (r > 0.99). PMA shifted the
O2 intercept of the
O2-PVA relation downward (an average
28% decrease; P < 0.05; see Fig. 2B) and
also decreased its slope (S). Consequently, PMA
significantly increased 1/S (the contractile efficiency) by an average of 41% (see Fig. 2C). Table
1 summarizes the changes in LV
mechanoenergetics before and 30 min after drug interventions. PMA
markedly increased coronary vascular resistance, which resulted in an
increase of 58% in the CPP required to maintain constant coronary flow
and decreased developed pressure by 44%. KCl-arrested basal metabolic
O2 after PMA was not significantly
different from that in the control state. This result indicates that
the decrease in PVA-independent O2 after
PMA was primarily due to a decrease in
O2 for E-C coupling. Moreover,
KCl-arrested basal metabolic O2 was not
significantly different before and after perfusion with each treatment.
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O2 intercept of the
O2-PVA relationship. L-NNA
administration increased coronary vascular resistance to a similar
extent as PMA, required a similar increase in CPP to maintain constant
flow, and decreased Emax by 12%.
L-NNA shifted the O2
intercept of the O2-PVA relation
downward by a modest amount, but contractile efficiency remained
unchanged (P = 0.81). Thus the PMA-induced decrease in
the slope of the O2-PVA relationship
cannot be ascribed to increased coronary resistance or perfusion pressure.
To determine whether PMA-induced coronary vasoconstriction caused
myocardial ischemia even though coronary flow was kept
constant, we measured lactate concentration in the coronary effluent
before and after PMA infusion (n = 4). There was no
detectable lactate (<0.2 mM) before and after PMA infusion.
Furthermore, as shown in Fig. 3, there
was no correlation between the increase in contractile efficiency and
the increase in CPP after PMA treatment [correlation coefficient
(r) = 0.14].
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Effect of chelerythrine on PMA-induced decreases in
O2 intercept and increases in
contractile efficiency.
To explore the subcellular mechanism by which PMA increases
contractile efficiency, we examined the effect of pretreatment with
chelerythrine. As summarized in Table 1, this agent alone did not alter
contractile efficiency, Emax, or PVA-independent O2. As shown in Figs.
4 and 5,
after chelerythrine pretreatment, PMA did not alter CPP,
Emax, the O2
intercept of the O2-PVA relationship, or
contractile efficiency. Thus chelerythrine abolished PMA-induced
coronary vasoconstriction, negative inotropy, and increases in
chemomechanical conversion efficiency.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, we demonstrated that administration of PMA
decreased Emax and PVA-independent
O2 (the
O2 intercept of the
O2-PVA relation). The decrease in
Emax averaged 30%, a magnitude of depression of
contractility comparable to that observed in heart failure. Because
basal metabolism was unchanged after PMA treatment, the decrease in
PVA-independent O2 was primarily due to
a decrease in O2 for E-C coupling.
Concomitantly, PMA increased contractile efficiency in a manner
independent of changes in coronary resistance or perfusion pressure.
Chelerythrine, a PKC inhibitor, abolished the PMA-induced negative
inotropy, decrease in PVA-independent
O2, and increase in contractile efficiency.
PMA and cardiac contractility. Most phorbol-ester studies in myocardial preparations have reported negative inotropic effects (6, 20, 35, 37). However, there are a few reports of positive inotropic effects; Karmazyn and Haist (19) and Macleod and Harding (23) reported that 10 pM and 100 nM PMA produced a positive inotropic effect in isolated rat hearts and rat ventricular myocytes, respectively. In contrast, in preliminary experiments, we observed no effect of 10 pM PMA on contractility or perfusion pressure in our preparation (data not shown). The reasons for these apparent discrepancies are unclear.
Although we did not measure PKC activity directly, our results indicate that PMA in fact was exerting its effect via stimulation of PKC. Capogrossi and colleagues (6) reported that a 10-min exposure of rat ventricular myocytes to 10 nM PMA was associated with a 1.5-fold increase in membrane-associated PKC activity. In the present study, the negative inotropy and coronary vasoconstriction produced by 10 nM PMA was completely attenuated by the specific PKC inhibitor chelerythrine (15).
The negative inotropic effect of PMA in our preparation could possibly have been due to PMA-induced coronary vasoconstriction resulting in myocardial ischemia. Several lines of evidence suggest this is unlikely. First, the hearts were perfused under constant-flow conditions to minimize this possibility. Second, PMA did not produce any upward shift of the diastolic pressure-volume relation, which would be expected during ischemia. Last, PMA perfusion for 30 min did not induce myocardial lactate production as was measured in the coronary effluent. Our metabolic results are consistent with the results of Watson and Karmazyn (35), who reported only minor effects of a similar concentration of phorbol ester on high-energy phosphates in isolated rat hearts. Thus we conclude that the negative inotropic effect was not mediated by ischemia but is a direct myocardial action of PMA.
We observed increased EDP with both high CPP and L-NNA infusion but not with PMA. In the high-CPP experiments, coronary flow was increased to raise CPP. The increased EDP is consistent with an increase in myocardial turgor. In PMA and L-NNA experiments, CPP was varied while coronary flow was maintained constant. Because altered flow (not CPP) is the main mechanism of turgor-mediated changes in filling pressure (2), the lack of EDP change in the PMA-infusion group was expected. The increase in EDP with L-NNA may have been related to the fact that NO decreases myofilament calcium sensitivity (30). Hence, decreased NO production may have increased EDP due to a calcium-sensitizing effect analogous to what is observed with calcium-sensitizing drugs (16).
Effect of PMA on PVA-independent O2.
The O2 intercept of the
O2-PVA relation (PVA-independent
O2) is considered to represent
O2 used for E-C coupling (mainly sarcoplasmic reticulum Ca2+ reuptake) and basal metabolism
(31). We observed a decrease in PVA-independent
O2 after PMA perfusion. Because basal
O2 was unchanged, this likely reflects
depressed Ca2+ cycling induced by PMA. Suga and colleagues
(32) reported that ischemia resulting from
decreased CPP (
40 mmHg) resulted in a decrease in PVA-independent
O2 and a progressive decrease in Emax. In our experiments, however, in which CPP
was increased at constant flow, there was once again no evidence of
ischemia. PMA may modulate (either directly or via PKC
activation) the sarcoplasmic reticulum Ca2+ pump as well as
the L-type calcium channel (8, 9, 28). Because decreases
in PVA-independent O2 produced by PMA
were completely attenuated by chelerythrine, the PMA-induced decrease in PVA-independent O2 also appears to
result predominantly from a direct action of PKC and suggests a
significant in vivo role for PKC activation in modulation of calcium
handling. In view of the fact that the L-NNA-induced
increase in coronary resistance was associated with a modest decrease
in PVA-independent O2 (much smaller than
that observed with PMA), increased coronary resistance per se could
also have contributed to the PMA-induced decrease.
Effect of PMA on contractile efficiency.
One of the most important findings of the present study is that PMA
decreased the slope of the O2-PVA
relation, which indicates an increase in the energy conversion
efficiency of the contractile machinery. Suga and colleagues
(32) reported that substantial decreases in CPP altered
the slope of the O2-PVA relation. This raises the possibility that the PMA-induced increase in coronary resistance and the resultant increase in CPP could have influenced contractile efficiency. However, we showed that there was no
correlation between the increase in contractile efficiency and the
increase in CPP. To further clarify whether increased CPP and/or
coronary resistance influence contractile efficiency, we increased CPP directly by increasing the coronary perfusion pump speed or by perfusing L-NNA in a dose that resulted in a similar
increase in resistance as PMA, thus requiring a similar increase in CPP to maintain constant coronary flow. Because neither maneuver altered the slope of the O2-PVA relation, it is
unlikely that PMA-induced vasoconstriction was the cause of the change
in contractile efficiency.
O2 to ATP (the efficiency
of oxidative phosphorylation in synthesizing ATP) and of ATP to PVA
(the efficiency of the contractile machinery in generating total
mechanical energy by hydrolyzing ATP) (31), the increase
we observed could have occurred at either or both of these steps. As
discussed previously (see Effect of PMA on cardiac
contractility), a shift from an aerobic to an anaerobic state in
our studies is highly unlikely. Additionally, changes in myocardial
preference for metabolic substrates do not appear to affect the slope
of the O2-PVA relationship
(5), and there is no evidence that PMA influences
oxidative phosphorylation efficiency. From these lines of evidence, the
increased contractile efficiency is most likely due to an increased
efficiency of conversion of ATP to PVA.
Activation of PKC by PMA increases myofilament Ca2+
sensitivity through sarcolemmal Na+/H+
exchanger activation, which increases intracellular pH. Increased myofilament Ca2+ sensitivity could possibly influence
contractile efficiency. However, we previously reported
(16) that the Ca2+-sensitizing agent EMD-57033
does not affect contractile efficiency. Hata and co-workers
(14) reported a similar lack of effect of pimobendan. Thus
Ca2+ sensitization seems an unlikely explanation for the
effect of PMA on contractile efficiency.
Although PKC activation is implicated as the mechanism of the
PMA-induced increase in contractile efficiency, its underlying cause is
unclear. We propose that it is best explained by a direct effect of PKC
on cross-bridge kinetics at the level of the actomyosin reaction.
Lester and colleagues (22) reported that PMA and the diacylglycerol analog 1,2-dioctanoyl-sn-glycerol decrease
maximum velocity of unloaded shortening in skinned ventricular
myocytes, which is consistent with a decreased cross-bridge cycling
rate. Moreover, we have previously shown that increased myofibrillar ATPase activity induced by hyperthyroidism in rabbits and
associated with a marked increase in the proportion of the faster
ATPase -myosin heavy-chain (-MHC) isoform results in reduced
contractile efficiency (12). Correspondingly, we have also
shown that the reduced myofibrillar ATPase activity that is
characteristic of failing myocardium (in Dahl salt-sensitive rats) is
associated with increased efficiency (18). Thus changes in
myofibrillar ATPase activity cause directionally opposite changes in
efficiency. Similar results are reported in failing human myocardium in
which depressed myofibrillar ATPase activity is associated with
increased contractile economy (1, 26). PKC-mediated
phosphorylation of several sarcomeric proteins modulates myofibrillar
ATPase activity. PKC phosphorylates troponin I (at different sites than
PKA), which results in inhibition of actomyosin ATPase
(33). PKA-mediated phosphorylation of myosin-binding
protein C results in decreased actomyosin ATPase activity in hearts
with substantial amounts of -MHC as is present in the rat
(36). Because PKC phosphorylates myosin binding protein C
at the same sites as PKA (33), it is likely that PKC
activation also decreases ATPase activity via this mechanism. Finally,
PKC phosphorylates troponin T (17, 27), and this also
depresses ATPase activity. One or more of these effects of PKC on
contractile proteins is likely responsible for the increased
contractile efficiency we observed.
Many neurohormones whose activities are known to be elevated in failing
myocardium [-adrenergic agonists, endothelin-1 (ET-1), angiotensin
II] activate PKC and may therefore also function to increase
contractile efficiency (7, 29). McClellan and co-workers (25) have made the intriguing observation using cryostat
sections of quick-frozen rat hearts that ET-1 decreases actomyosin
ATPase activity, and they have predicted that ET-1 increases the
efficiency of contraction. Thus ET-1 may increase contractile
efficiency by decreasing ATPase activity through PKC-mediated
phosphorylation of contractile proteins. However, Gando and colleagues
(10) reported that ET-1 (100 nM) does not phosphorylate
troponin I in intact, beating rat hearts. It will thus be of interest
to determine whether or not ET-1 and other neurohormones have an effect
on contractile efficiency in vivo.
Clinical implications. In summary, our study demonstrates that PMA exerts a negative inotropic effect through activation of PKC. At the same time, PKC activation also improves chemomechanical conversion efficiency. To the extent that PKC activation is a component of heart failure, its effects on the myocardium are likely to be mixed. Depressed cross-bridge cycling certainly contributes to contractile failure. However, in view of the fact that failing myocardium has reduced energy reserves (21), the associated increase in contractile efficiency can be considered beneficial. Which of these effects are ultimately more important remains to be determined.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant RO1 HL-50287.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. M. LeWinter, Cardiology Unit, Fletcher Allen Health Care/MCHV Campus, 111 Colchester Ave., Burlington, VT 05401 (E-mail: martin.lewinter{at}vtmednet.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 2 February 2001; accepted in final form 10 July 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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