(Circulation. 1999;99:570-577.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Effects of a Specific Endothelin-Converting Enzyme Inhibitor on Cardiac, Renal, and Neurohumoral Functions in Congestive Heart Failure
Comparison of Effects With Those of Endothelin A Receptor Antagonism
From the First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan.
Correspondence to Atsuyuki Wada, MD, First Department of Internal Medicine, Shiga University of Medical Science, Tsukinowa, Seta, Otsu, Japan, 520-2192. E-mail wada{at}belle.shiga-med.ac.jp
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Abstract |
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Background—Endothelin (ET)-1 is generated from big ET-1 by endothelin-converting enzyme (ECE). Plasma big ET-1 and ET-1 levels are strongly related to survival in patents with congestive heart failure (CHF). Because selective enzymatic processing of ET-1 formation appears to be an important therapeutic target for CHF, we investigated the acute effects of a specific ECE inhibitor on cardiorenal and endocrine functions in CHF compared with those of a selective ETA receptor antagonist.
Methods and Results—CHF was induced in beagle dogs by rapid right ventricular pacing (270 bpm, 14 days). Two incremental doses of a specific ECE inhibitor, FR901533, or a selective ETA receptor antagonist, FR139317 (1 and 3 mg/kg, n=8, respectively), were injected into dogs with CHF. FR901533 and FR139317 decreased mean arterial pressure and pulmonary capillary wedge pressure associated with reduction in systemic and pulmonary vascular resistance. These agents increased cardiac output but did not affect left ventricular fractional shortening. FR139317 exerted a greater depressor effect on mean arterial pressure than FR901533 (P<0.05). These agents decreased plasma atrial natriuretic peptide levels, but only FR901533 decreased plasma renin activity, angiotensin II, and aldosterone levels. Neither agent changed the plasma norepinephrine level despite the fall in blood pressure. These drugs increased the urinary water and sodium excretion rate associated with increases in the glomerular filtration rate and renal plasma flow, and the incremental magnitude induced by FR139317 was larger than that by FR901533 (P<0.05).
Conclusions—An ETA receptor antagonist appeared to induce greater vasodilative effects on systemic and renal vasculature in CHF than an ECE inhibitor. However, the ECE inhibitor reduced the secretion of neurohumoral factors that are activated in proportion to the severity of CHF. Our acute complementary data may support the importance of the role of ECE in CHF and provide a rationale foundation for investigating the usefulness of long-term treatment with ECE inhibitors in CHF.
Key Words: endothelin • heart failure • enzymes • receptors • hormones
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Introduction |
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Endothelin (ET)-1, the most powerful endothelium-derived vasoconstrictor, is generated as prepro ET-1 that is enzymatically cleaved to form an intermediate, big ET-1, and big ET-1 is further processed to form the biologically active mature ET-1 by a specific phosphoramidon-sensitive metalloprotease called endothelin-converting enzyme (ECE).1 2 Significant elevations of plasma big ET-1 and ET-1 levels are observed in congestive heart failure (CHF) compared with those in normal control subjects, and these variables are strongly related to survival in CHF patients.3 4 Indeed, long-term treatment with some selective ETA and mixed ETA/B receptor antagonists greatly improved the survival of rats with CHF.5 6 Considering the evidence that both ETA and ETB receptors mediate vasoconstriction in some vessels,7 we can anticipate an alternative option of anti-ET therapeutic strategy, that is, blocking the generation of ET-1 by an ECE inhibitor. Indeed, brachial administration of phosphoramidon, an ECE inhibitor, caused forearm vasodilation and increased forearm blood flow in patients with CHF.8 However, the compound is not a selective inhibitor; rather, it is more of a neutral endopeptidase than an ECE inhibitor, and no specific ECE inhibitors have been developed so far. Systemic administration of ECE inhibitors blocks all biologically active ET-1 actions including both ETA and ETB receptor-mediated ET-1 actions. However, we previously reported that the selective ETB receptor antagonist RES-701-1 increased systemic and pulmonary vascular resistance and decreased cardiac output (CO) in CHF.9 Therefore it should be evaluated whether there are any adverse effects from inhibiting the ET system at the level of ECE and whether specific ECE inhibition is really a useful treatment for CHF. A specific ECE inhibitor, FR901533, which has greater potency and selectivity for ECE than phosphoramidon, has been synthesized.10 11 Our principal objective was to evaluate whether the modulation of the production of ETs with the specific ECE inhibitor has beneficial effects in treating CHF, as ET receptor antagonists have shown. We examined the acute effects of FR901533 on hemodynamic, neurohumoral, and body fluid regulation by comparing those effects of a selective ETA receptor antagonist, FR139317, in dogs with CHF induced by rapid right ventricular pacing.
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Methods |
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Animal Preparation
Conditioned beagles of either sex, weighing 10 to 13 kg, were used for all experiments, as previously described.12 This study was approved by the Animal Research Committee of Shiga University of Medical Science. After anesthesia was induced with pentobarbital sodium (25 mg/kg), the dogs were ventilated with a respirator (Aika R-60). Through a left thoracotomy, the heart was exposed and 2 pacemaker leads (Matsuda M-23) were sutured onto the right ventricular apex. After the incision was closed, the leads were tunneled to the back and connected to an external pacemaker (Seamed 540). The left femoral vein was then exposed and a thermodilution catheter (Goodtec T-047-03) was advanced into the pulmonary artery to measure right atrial pressure (RAP), mean pulmonary arterial pressure (MPAP), pulmonary capillary wedge pressure (PCWP), and CO. A Tygon catheter (Norton R3603) was placed in the descending thoracic aorta through the left femoral artery to measure mean arterial pressure (MAP). The right jugular vein was also catheterized, and the Tygon catheter was advanced into the vena cava for drug administration. All of those chronic catheters were implanted percutaneously and flushed with heparin-saline 3 times per week. The pacemaker and the ends of the catheters and pacing wires were securely fastened in a small bag worn on the back of the animal. After recovering from instrumental surgery for at least 14 days, study 1 was performed. The day after the completion of study 1, normal baseline measurements were taken and the pacemaker was programmed to an asynchronous mode at a rate of 270 bpm and pacing continued for 14 days for study 2.
CO was assessed in triplicate by the thermodilution technique with a Gould CO computer (Statham SP1435). Systemic vascular resistance was calculated as [(MAP-RAP)x80]/CO and pulmonary vascular resistance as [(MPAP-PCWP)x80]/CO. A 2-dimensional and M-mode echocardiogram (Toshiba SAL-77A, 2.5-MHz transducer) was performed from a right parasternal approach to image the left ventricle. The left ventricular (LV) fractional shortening was calculated as the ratio of [(LV end-diastolic diameter-LV end-systolic diameter)/LV end-diastolic diameter]x100. Blood was drawn from the pulmonary artery through the thermodilution catheter and transferred to specially prepared tubes stored on ice for analysis of plasma big-ET-1, ET-1, atrial natriuretic peptide (ANP), angiotensin II, aldosterone, and norepinephrine concentrations and plasma renin activity (PRA). The blood specimens were centrifuged at 4°C and the plasma was frozen at -30°C until assay. All subsequent studies were performed with animals in the conscious state.
Experimental Protocol
Study 1: Inhibitory Pressor Effects of FR901533 in
Response to Big ET-1 and ET-1
The selective nature of FR901533 as an ECE inhibitor
has been demonstrated to be at least 3 times more potent than
phosphoramidon in ECE inhibition of bovine
endothelial cells and to inhibit both ECE-1 and ECE-2
activities with similar potencies.2 10 13 FR901533
interacted with metallopeptidase at nanomolar concentrations and did
not inhibit neutral endopeptidase and
collagenase activities, whereas
phosphoramidon is 
50 times more active against
neutral endopeptidase than ECE.11
To confirm the in vivo effects of FR901533 as an ECE
inhibitor, we observed the inhibitory effects
of it on MAP responses to exogenously administered human big ET-1 or
ET-1 (Peptide Institute). The criterion for the initial dose selection
of FR901533 was to block the pressor response to big ET-1 that produced
a rise in MAP of 
15 mm Hg from the pretreatment blood pressure.
Eight dogs were randomly selected and studied after complete recovery
from the effects of surgery. After the hemodynamics had
stabilized, big ET-1 (0.2 nmol/kg, n=4) or ET-1 (0.75 nmol/kg, n=4)
alone was injected as a bolus. After 3 days of the first study,
FR901533 (Fujisawa Pharmaceutical Co, Ltd, 1 mg/kg) was administered to
each dog 5 minutes before big ET-1 or ET-1 was injected. Changes in MAP
in response to big ET-1 or ET-1 were recorded for 60 minutes in
each group without rapid pacing.
Study 2: Cardiorenal and Hormonal Effects of ECE
Inhibitor and ETA Antagonist in Dogs With
CHF
After inducing CHF with 14 days of rapid pacing, we compared the
acute effects of the ECE inhibitor with those of selective
ETA receptor antagonist on the changes in
hemodynamics, hormones, and renal functions in CHF. We
divided the dogs with CHF into 3 groups; the ECE inhibitor
group (n=8) was given FR901533, the ETA block group (n=8) was
administered a selective ETA receptor antagonist, FR139317
(Fujisawa Pharmaceutical Co, Ltd), and the vehicle group (n=5) received
only saline as a control. All subsequent measurements were recorded
with ongoing rapid ventricular pacing. As previously
reported, the urinary bladder was catheterized with a CLINY balloon
tube (Create Medic Co) under brief thiopental sodium
anesthesia (4 mg/kg); 45 minutes later, a priming dose of
50 mg/kg creatinine and 8 mg/kg
para-aminohippurate dissolved in a 10-mL saline solution was
infused over a period of 10 minutes.12 This was
followed by a constant infusion (0.75 mL/min) of 1.0 mg/kg per minute
creatinine and 0.3 mg/kg per minute
para-aminohippurate throughout the experimental period.
After a 60-minute equilibration period, the first of 2 clearance
periods was performed, each of which lasted for 20 minutes. After 2
sequential baseline periods, in the ECE inhibitor group,
the first bolus dose of FR901533 at 1 mg/kg dissolved in a 20-mL saline
solution was administered intravenously. After 30 minutes,
the second dose of 3 mg/kg was injected, and two 30-minute clearances
were allowed for each dose. In the ETA block group, FR139317 was
administered at 1 and 3 mg/kg, given at intervals of 30 minutes in the
same way. FR139317 at a dose of >1 mg/kg has previously been shown to
inhibit endogenous ET-1 activity through ETA
receptors.9 In the vehicle group, saline solution was
administered at intervals of 30 minutes to exclude any temporal
effects. During each clearance period, the pressure
parameters were recorded every 5 minutes. CO and blood
sampling were performed at the end of each clearance period. An
echocardiogram was performed to estimate changes in LV fractional
shortening at the baseline and the end of all the experiments during a
brief cessation of rapid pacing.
Analysis of Blood and Urine Samples
The plasma big ET-1 concentration was measured by ELISA with a
commercial kit (Biomedica Gesellschaft). Plasma (500 µL) was
precipitated and dried in a Speed Vac concentrator (Savant SC110A).
Peptides were reconstituted with 500 µL of assay buffer and were
subjected to ELISA. One hundred microliters of samples and 50 µL of
monoclonal detection antibody were simultaneously added to
the kit wells precoated with a polyclonal rabbit antibody to human big
ET-1. Big ET-1 was quantitated by an enzyme-catalyzed color change
detectable on the ELISA reader (Titertek Multiskan MCC/340 MK II) at
450 nm filter. The intra-assay and interassay coefficients of variation
were 3.9% (n=11) and 6.1% (n=12). The plasma ET-1 concentration was
determined by radioimmunoassay as previously described.14
Blood for PRA, angiotensin II, aldosterone, and
ANP assay was measured by radioimmunoassay as previously
described.3 12 15 16 Plasma norepinephrine
concentration was performed by high-performance liquid
chromatography, as previously reported.12
Serum and urine creatinine, para-aminohippurate,
and sodium concentrations were measured as previously
reported.12 Creatinine clearance and
para-aminohippurate clearance were calculated with standard
formulas and were equated with glomerular filtration rate
(GFR) and renal plasma flow (RPF), respectively.
Statistical Analysis
All data are presented as mean±SEM. ANOVA for repeated
measurements was used to determine the significance of changes during
multiple time-dependent observations. Comparisons with baseline values
were analyzed by Dunnett's test after ANOVA for repeated
measurements. Student's t test was used to analyze
the significance of single comparisons. A value of P<0.05
was considered significant.
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Results |
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Blocking Effects of FR901533 on Big-ET-1 and ET-1 Injection
The effects of FR901533 on big ET-1–induced or ET-1–induced changes in MAP are shown in Figure 1
.
ET-1 elicited an initial transient depressor response followed by
sustained hypertension, whereas big ET-1 induced a prolonged pressor
response similar to that induced by ET-1, but there was no initial
transient depressor effect. Pretreatment with FR901533 significantly
blocked the big ET-1–induced pressor response, but FR901533 did not
affect the ET-1–induced initial hypotensive and subsequent
hypertensive effects.
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) on changes in
MAP from normal baseline induced by big ET-1 (n=4, 
) or ET-1 (n=4,
) in dogs without heart failure. FR901533 (1 mg/kg) was administered
intravenously 5 minutes before intravenous big
ET-1 (0.2 nmol/kg) or ET-1 (0.75 nmol/kg) administration.
*P<0.05, 
P<0.01 compared with
baseline, #P<0.05 compared with big ET-1 group.
Characteristics of CHF
Hemodynamic and endocrine characteristics in
normal dogs, just before initiation of rapid ventricular
pacing and again after induction of CHF, are summarized in Table 1. After 2 weeks of rapid pacing, PCWP
and RAP were significantly increased, but MAP and CO were decreased
relative to the respective normal values in all the groups. The LV
fractional shortening was also decreased compared with that in normal
control subjects. The secretion of ET-1 in plasma was increased
2-fold after rapid pacing, thus the endogenous ET system
may have been activated compared with that in the normal state.
The PRA and ANP, aldosterone, and
norepinephrine levels were also significantly increased. In
addition to the deteriorated hemodynamics and
activated hormonal secretion, all of the dogs were judged to
have CHF on the basis of evidence of anorexia and ascites. When the
hemodynamic and hormonal data of all experimental
animals were pooled, differences among the 3 groups were not
significant.
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Effects of ECE Inhibitor and ETA Block on Plasma Big
ET-1 and ET-1 Levels in CHF
We investigated the changes in plasma big ET-1 and ET-1
concentrations as a marker to demonstrate inhibition of the conversion
of big ET-1 to ET-1. As shown in Figure 2, administration of FR901533
significantly increased plasma big ET-1 concentrations
(P<0.05) but did not affect plasma ET-1 levels in dogs with
CHF. In contrast, FR139317 did not influence either peptide level.
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Hemodynamic Effects of ECE Inhibitor
and ETA Block in CHF
Hemodynamic responses to 2 incremental doses of
ECE inhibitor or ETA blocker are shown in Figure 3. FR901533 and FR139317 induced
significant decreases in MAP and PCWP and increased CO associated with
significant reductions in systemic and pulmonary vascular
resistance. The compounds did not significantly change RAP throughout
the experiment. However, the ETA receptor antagonist
exerted a greater depressor effect on MAP than the ECE
inhibitor at a higher dose (P<0.05). These
agents did not affect LV fractional shortening, from 11±1 to 12±2 and
from 12±1 to 12±2, nor did they affect heart rate, from 140±4 to
135±16 and from 145±4 to 150±10 bpm, respectively.
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P<0.01,
Hormonal Effects of ECE Inhibitor and ETA Block in
CHF
Hormonal responses to FR901533 and FR139317 are shown in Figure 4. Both compounds caused significant
decreases in plasma ANP levels with modest reductions in PCWP. Only
FR901533 significantly decreased PRA (P<0.05),
angiotensin II (P<0.05), and
aldosterone levels (P<0.01). Despite the
decrease in blood pressure, neither drug changed the plasma
norepinephrine levels from 811±102 to 710±94 and from
780±141 to 742±103 pg/mL, respectively.
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Renal Effects of ECE Inhibitor and ETA Block in
CHF
The effects of FR901533 and FR139317 on renal functions are shown
in Table 2. Both compounds significantly
increased the urine flow rate and absolute urinary sodium excretion
compared with the average basal values. These agents also significantly
increased GFR and RPF; however, FR139317 caused greater increases in
those values than FR901533 (P<0.05).
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Discussion |
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Considering that anti-CHF therapy is not totally successful in reducing mortality rates, the ET system is an attractive target for therapeutic intervention in CHF because long-term treatment with ET receptor antagonists has improved survival in rats with CHF.5 6 However, it was reported that the density and affinity of ET receptors were altered in CHF,17 and long-term treatment with ET receptor antagonists may not always exert consistent efficacy in CHF. Another area of research on alternative anti-ET agents involves ECE inhibition. The identification of the potential usefulness of ECE inhibition in CHF is an important objective of our study compared with the acute effects of an ETA receptor antagonist on hemodynamics, neurohumoral functions, and body fluid balance.
Although there is no direct index showing the inhibition of conversion of big ET-1 to ET-1 in vivo, ECE inhibition may theoretically increase plasma big ET-1 and decrease plasma ET-1 levels. When we administered FR901533, which blunted the big ET-1-induced pressor effect, the apparent rise in plasma big ET-1 levels can serve as a marker of considerable inhibition of conversion to ET-1 in intact animals. Failure of plasma ET-1 level to decrease with ECE inhibitor may be due do the oversaturated clearing capacity or the downregulation of ETB receptors, which mediated endocytosis of ET-1.18 A longer duration of ECE inhibition may be required to lower plasma level of ET-1.
Changes in Hemodynamics in CHF
An ECE inhibitor, phosphoramidon
reduced pulmonary hypertension after cardiopulmonary
bypass in pigs,19 and it caused substantial forearm
vasodilatation in patients with CHF.8 However, the
vasodilative action of phosphoramidon could be due, in
part, to the effect of ANP as a result of inhibition of neutral
endopeptidase activity. Since we demonstrated that an
important vasodilative action involving ETB receptors exists in CHF and
that a selective ETB receptor blockade could be harmful to
hemodynamics,9 it is necessary to examine
the effects of specific ECE inhibitors on
hemodynamics. FR901533 slightly but significantly
reduced MAP and PCWP in association with a decrease in systemic and
pulmonary vascular resistance. These results suggest that the
ET system overall acts as a vasoconstrictor in CHF. However, an ETA
receptor antagonist, FR139317, caused a greater decrease in
MAP than did FR901533. This may be due to the fact that the ECE
inhibitor blocked the vasodilative effect mediated by ETB
receptors and/or the ETA receptor antagonist blocked the
vasoconstrictive effect of ET-1 and might
simultaneously augment the vasodilative effect through the
ETB receptor. Because ET-1 has a positive inotropic effect on cardiac
muscle, both compounds theoretically elicit a negative inotropic
effect. However, these agents did not change LV fractional shortening
in the present study. Thomas et al20 and Spinale
et al21 reported that ET-1 caused a dose-dependent
decrease in myocyte contractile function and that long-term
administration of ETA receptor antagonist improved isolated
myocyte contractility and normalized inotropic
responsiveness in rapid pacing–induced CHF. Both compounds may alter
loading conditions and produced greater hemodynamic
beneficial effects; however, long-term investigation is needed to
evaluate whether the anti-ET therapy has beneficial effects on myocyte
contractile function in CHF.
Changes in Neurohumoral Factors in CHF
To determine whether ECE inhibition has a therapeutic
potential in treating CHF, it might be helpful to assess the effects on
neurohumoral integration of the ET system. If FR901533 is merely a
vasodilator, it will result in reflex activation of the
vasoconstrictive endocrine system. However, the agent
did not change the plasma norepinephrine levels despite a
fall in blood pressure. Furthermore, the ECE inhibitor but
not the ETA receptor blocker significantly decreased PRA,
angiotensin II, and aldosterone levels.
Although ET-1 directly inhibited renin release by increasing calcium
influx in juxtaglomerular cells,22 the
decrease in PRA appeared to be mediated by both the macula densa
mechanism and increased RPF in the present study. In contrast, ET-1
enhanced the conversion of angiotensin I to
angiotensin II in cultured endothelial
cells23 and directly stimulated aldosterone
secretion in the adrenal zona glomerulosa.24 Despite
blocking the beneficial ETB receptor–mediated vasodilative action, the
fact that FR901533 reduced the vascular resistance may partly involve
the subsequent decrease in angiotensin II–mediated
vasoconstriction. ET-1 appeared to be involved in the complicated
modulation of the renin-angiotensin-aldosterone
(RAA) system, and further studies are required to address whether the
ET system directly regulated secretions of the RAA system through ECE
or ETB receptors. Because those neurohumoral factors are
activated in proportion to the severity of CHF and are
prognostic indicators in patients with CHF,25 the decline
in the hormone levels with FR901533 may indicate that an ECE
inhibitor can attenuate aggravation of CHF.
Changes in Renal Functions in CHF
Exogenous ET-1 increases renal vascular resistance and falls
in RPF and GFR, thereby reducing urine
production.26 We demonstrated that an ETA receptor
antagonist improved renal hemodynamics as
well as water and sodium, whereas an ETB receptor
antagonist decreased RPF in this canine
model.9 In rats with ischemic renal failure,
phosphoramidon restored the GFR, ameliorating the
reduction of urine flow and RPF.27 In the present
study, FR901533 significantly increased the urinary flow rate, sodium
excretion rate, GFR, and RPF, similar to the effects induced by
FR139317. An ECE inhibitor may be useful in treating body
fluid retention associated with CHF; however, the renal vasodilative
effect of an ETA receptor antagonist appeared to be greater
than that of an ECE inhibitor, similar to its effect on the
systemic vasculature. Sodium and water excretion are also regulated by
ANP and the RAA system. Although both compounds decreased the plasma
ANP level, the increases in RPF and GFR may have exceeded the reduction
in ANP-induced diuresis and natriuresis. Because
angiotensin II reduces RPF by vasoconstriction and
angiotensin II and aldosterone regulate
extracellular fluid volume by their effects on sodium
retention,28 the improved renal functions with ECE
inhibition might partly be due to suppression of the RAA system.
Limitations of the Study
There are several limitations of the present study.
First, because the development of tachycardia-induced CHF
is reversible and the termination of rapid pacing resulted in
improvement of cardiac and hormonal functions,29 it would
have become difficult to distinguish changes caused by the ECE
inhibitor and ETA receptor antagonist from the
effects of deactivating the pacing. Thus we performed these experiments
with ongoing rapid pacing. However, rapid ventricular
pacing is associated with markedly asynchronous ventricular
wall motion, rendering accurate M-mode
echocardiographic measurements difficult. Therefore, we
measured the LV fractional shortening during sinus rhythm only. Second,
the geometric shape of the LV cavity in our
tachycardia-induced CHF model is far more complicated than
a sphere and, even after the termination of pacing, there is a problem
involving the validity of LV volume calculations. Although LV
fractional shortening is one way of describing the quality of LV
contractions, it does not equate to the stroke volume measured by the
thermodilution technique. Third, a higher dose of FR901533 was expected
to exert more favorable effects; however, it did not induce any further
effects on MAP or PCWP. We were concerned about excessive hypotension,
which would cause reflex activation of the
vasoconstrictive hormones and decreased urine output if
we administered a much higher dose of FR901533. FR901533 is an
expensive and scarce compound; therefore, we could not evaluate the
long-term or the higher dose–effects in large animals.
In conclusion, because CHF is a chronic disease, the therapeutic modality of ECE inhibition should be evaluated by long-term treatment of a specific ECE inhibitor, not the short-term effects. However, to our knowledge, it has not been demonstrated that specific ECE inhibition had acute beneficial effects on cardiorenal and neurohumoral functions in CHF. An ETA receptor antagonist appeared to induce greater vasodilative effects on systemic and renal vasculature in CHF than ECE inhibition. However, the ECE inhibitor reduced the secretion of neurohumoral factors, which are activated in proportion to the severity of CHF. Therefore, even though the vasodilative effect of an ECE inhibitor may be less than that of an ETA receptor antagonist, ECE inhibition may have demonstrated favorable potential in dogs with CHF. Our complementary data may support the importance of the role of ECE in generating ET-1 in CHF and provide a rational foundation for investigating the usefulness of long-term treatment with ECE inhibitors in CHF.
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Acknowledgments |
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This study was supported by a grant from the Special Project for the Promotion of Education from Shiga University of Medical Science, by a grant-in-aid for Scientific Research (B) (08457206), and a grant-in-aid for Encouragement of Young Scientists (09770481) from the Ministry of Education, Science, Sports, and Culture of Japan. We wish to thank Ikuko Sakaguchi for excellent technical assistance. We are also grateful to Fujisawa Pharmaceutical Co, Ltd, Japan, for supplying FR901533 and FR139317.
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Footnotes |
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Guest Editor for this article was Dr James Scheuer, Albert Einstein College of Medicine, Bronx, NY.
Received March 24, 1998; revision received September 8, 1998; accepted September 17, 1998.
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