Published online before print April 27, 2001, doi: 10.1161/hh0901.089882
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© 2001 American Heart Association, Inc.
Article |
Cardiac Angiotensin II Formation in the Clinical Course of Heart Failure and Its Relationship With Left Ventricular Function
From Clinica Medica Generale e Cardiologia (G.G.N.S., M.B., I.C., S.V., M.C., M.L.P., B.B., I.B., G.P., P.A.M.), University of Florence, and Institute of Thoracic and Cardiovascular Surgery (T.T., M.M.), University of Siena, Italy.
Correspondence to Gian Gastone Neri Serneri, MD, Clinica Medica Generale e Cardiologia, University of Florence, Viale Morgagni 85, 50134 Florence, Italy.
Abstract
Abstract—In 76 patients with heart failure (HF) (New York Heart Association [NYHA] classes I through IV) and in 15 control subjects, cardiac angiotensin II (Ang II) generation and its relationship with left ventricular function were investigated by measuring aorta–coronary sinus concentration gradients of endogenous angiotensins and in a part of patients by studying 125I-labeled Ang I kinetics. Gene expression and cellular localization of the cardiac renin-angiotensin system components, the density of AT1 and AT2 on membranes and isolated myocytes, and the capacity of isolated myocytes for synthesizing the hypertrophying growth factors insulin-like growth factor-I (IGF-I) and endothelin (ET)-1 were also investigated on 22 HF explanted hearts (NYHA classes III and IV) and 7 nonfailing (NF) donor hearts. Ang II generation increased with progression of HF, and end-systolic wall stress was the only independent predictor of Ang II formation. Angiotensinogen and angiotensin-converting enzyme mRNA levels were elevated in HF hearts, whereas chymase levels were not, and mRNAs were almost exclusively expressed on nonmyocyte cells. Ang II was immunohistochemically detectable both on myocytes and interstitial cells. Binding studies showed that AT1 density on failing myocytes did not differ from that of NF myocytes, with preserved AT1/AT2 ratio. Conversely, AT1 density was lower in failing membranes than in NF ones. Ang II induced IGF-I and ET-1 synthesis by isolated NF myocytes, whereas failing myocytes were unable to respond to Ang II stimulation. This study demonstrates that (1) the clinical course of HF is associated with progressive increase in cardiac Ang II formation, (2) AT1 density does not change on failing myocytes, and (3) failing myocytes are unable to synthesize IGF-I and ET-1 in response to Ang II stimulation.
Key Words: angiotensins • congestive heart failure • AT receptors • failing myocytes • cardiomyopathy
Conclusive evidence has been presented that all of the components required for angiotensin II (Ang II) production are present in the human heart1 and that Ang II is continuously formed by cardiac tissues in healthy subjects.2 However, few studies have investigated the cardiac renin-angiotensin system (RAS) in human hypertrophy and heart failure (HF), as opposed to the large number of experimental studies performed in cell culture systems and experimental models (for studies, see Wollert and Drexler3 ). In human explanted failing hearts, levels of angiotensin-converting enzyme (ACE) mRNA,4 ACE activity, and ACE binding sites5 have been found to be increased as compared with control hearts. Levels of prorenin, renin, and ACE measured with enzyme kinetics are higher in failing than in control hearts.6 Although these studies provide important results, demonstrating that cardiac RAS is activated in explanted failing hearts, they do not provide information either about cardiac Ang II production during the clinical course of HF or about the relationship between Ang II and cardiac function. Moreover, these studies do not answer the critical question as to whether the enhanced cardiac expression of ACE actually promotes an increased production of Ang II, because several groups have challenged the notion that ACE is the major Ang II–forming enzyme in the human heart.7 8 A second open question is the identification of the cell types that actually express Ang II receptors in the failing myocardium and constitute the potential targets for Ang II receptor–mediated effects. Several groups have investigated the density of Ang II receptor subtypes in human failing hearts and have found a reduction in AT1,5 9 10 11 either without changes in AT29 10 or with an increase in them.5 11 However, these studies were only performed on myocardial homogenates, and no information is available on the regulation of Ang II receptor subtypes on myocytes and nonmyocyte cells. A last but no less important question is the functional significance of cardiac Ang II formation in myocardial hypertrophy and HF. Although Ang II has been most frequently associated with both experimental and human hypertrophy,12 13 14 the precise role of Ang II in cardiac hypertrophy remains elusive,15 16 because cardiac hypertrophy may develop in the presence of Ang II generation inhibitors or AT1 blockade.17 18 Moreover, human compensatory hypertrophy is associated with increased cardiac formation of insulin-like growth factor-I (IGF-I) in volume overload and endothelin (ET)-1 and IGF-I in pressure overload, but not with cardiac Ang II.14
Thus, the functional significance of ACE mRNA and increased ACE activity found in expanded hearts remains to be clarified. Therefore, the present study was planned with the following objectives: (1) to investigate whether and when cardiac Ang II formation increases during the clinical course of HF and its relationship with left ventricular function, (2) to identify and examine the distribution of Ang II receptor subtypes on myocytes and nonmyocyte cells from failing and nonfailing (NF) myocardium, and (3) to study the relationship between Ang II and the capacity of myocytes for producing the hypertrophying growth factors IGF-I and ET-1.
Materials and Methods
We investigated 76 patients with HF due to dilated
cardiomyopathy (DCM, n=36) or to ischemic
cardiomyopathy (ICM, n=40). Diagnosis of DCM
or ICM was based on clinical and echocardiographic
examination, cardiac catheterization, and
coronary angiography. HF patients were classified into
functional groups according to the New York Heart Association (NYHA)
classification
(Table 1
).
|
Patients with a recent history (<6 months) of myocardial infarction, a history of hypertension, echocardiographic evidence of valve or congenital heart disease, or an inability to suspend ACE inhibitors and diuretic treatment for 3 days were not considered for the study.
The control group was made up of 15 normotensive patients with atypical chest pain in whom angiography and routine diagnostic procedures did not reveal any abnormalities.
Cardiac specimens were obtained from 9 ICM and 13 DCM
patients in NYHA classes III (n=10) and IV (n=12), who underwent
cardiac transplantation, and 7 deceased donors with no history
or signs of heart disease, whose hearts could not be transplanted
because of surgical reasons or blood group incompatibility (NF hearts)
(Table 1
).
The protocol of this study complies with the principles of the Helsinki declaration. All patients gave their informed written consent to participate and to have their heart and blood samples used for the study. Echocardiographic and hemodynamic measurements were performed prospectively, as previously described.14
Cardiac formation of endogenous angiotensins was estimated as the aorta-coronary sinus gradient.14 Ang I and Ang II plasma concentrations were measured by RIA after HPLC separation as previously described.14 In 16 patients and 5 control subjects, the study of 125I-labeled Ang I (125I-Ang I) kinetics was simultaneously performed.14
Cardiomyocytes were isolated and membrane suspension was prepared from a noninfarcted portion of left ventricle free wall.19 All studies were performed on freshly isolated cells. Binding studies were performed at equilibrium using 125I-Ang II (100 pmol/L, 2000 Ci/mmol, Amersham) and selective AT1 (Valsartan, a kind gift of Dr V. Abbruscato, Novartis, Italy) or AT2 (PD-123319) antagonists.
mRNAs for renin, chymase, angiotensinogen (AGTN), ACE, AT1, and AT2 were quantified by reverse transcriptase–polymerase chain reaction (RT-PCR) using specific primers with GAPDH as internal standard14 and were expressed as the percentage of the values obtained in NF hearts.14 The in situ hybridization procedure was performed using specific cDNA photobiotin-labeled (Vector) probes.14 Myocardial cell types were identified by immunohistochemical methods using specific monoclonal antibodies. The presence of Ang II in myocardium was detected with the immunohistochemical method, using anti–Ang II rabbit antiserum (RIN 7002, Peninsula Laboratory, Inc). The stimulating effects of Ang II (10 nmol/L) on ET-1, IGF-I, and platelet-derived growth factor (PDGF) mRNA expression and peptide release by myocytes in vitro (100 000 myocytes/mL) were investigated in myocytes isolated from NF (n=4) and HF hearts (5 DCM and 4 ICM).
Data are mean±SD. Comparisons between groups were performed using 1-way ANOVA. For multivariate reevaluation of univariate correlations, the following were entered in a stepwise multiple regression analysis as independent variables, considering cardiac Ang II formation as a dependent variable: left ventricular end-diastolic diameter index, relative wall thickness, left ventricular mass index, left ventricular end-systolic volume index (LVESVI), left ventricular end-diastolic volume index (LVEDVI), left ventricular ejection fraction (LVEF), mean midwall velocity of circumferential fiber shortening (Vcf), end-systolic stress (ESS), end-diastolic stress, left ventricular end-diastolic pressure, Vcf/ESS ratio, Vcf/LVEDVI ratio, ESS/LVESVI ratio, and plasma renin activity (PRA).
An expanded Materials and Methods section can be found in an online data supplement available at http://www.circresaha.org.
Results
Cardiac Ang II Formation and
Ventricular Function
Cardiac production of Ang II, as expressed by
the mean aorta-coronary sinus concentration gradient, was
already mildly but significantly increased in NYHA class I patients and
further increased with the worsening of the functional class, with no
differences being found between DCM and ICM patients
(Figure 1A).
|
) and HF patients (
indicates ICM; •, DCM). Values under columns are mean±SD. *P<0.05 vs control subjects. B, Relationship between cardiac Ang II formation and ESS in HF patients.
The 125I-Ang I kinetics
parameters are reported in
Table 2. Neither extraction of both radiolabeled
angiotensins nor the 125I-Ang
I–to–125I-Ang II conversion rate differed
between patients and control subjects
(Table 2). Both Ang I and Ang II formation by cardiac
tissues were on average significantly
(P<0.01) higher in patients
with mild HF (NYHA classes I and II) than in control subjects and
further increased in patients with severe HF (NYHA classes III and IV;
P<0.01). The increased Ang I
de novo formation in patients with mild HF was mainly attributable to
cardiac tissues, given that Ang I formed by PRA during the
transcardiac passage of blood was not significantly
different from that of control subjects
(Table 2). In patients with severe HF, the total amount of
Ang I formed was further increased versus mild HF with an increase in
the contribution also by PRA
(Table 2). Cardiac Ang II formation measured by
125I-Ang I kinetics was highly correlated
with the aorta-coronary sinus gradient
(r=0.89,
P<0.001).
|
Ang II formation expressed by the aorta coronary
sinus gradient was usually increased in patients with reduced LVEF, but
it was found to be enhanced in a proportion of patients (18 of 76,
23%) with only mildly reduced LVEF (
40%), provided that ESS was
increased. Indeed, univariate regression analysis
showed that Ang II formation was negatively correlated with left
ventricular ejection fraction (LVEF,
r=-0.77,
P<0.001) and with the various
indexes of ventricular contractility (Vcf,
r=-0.72,
P<0.001; Vcf/ESS,
r=-0.75,
P<0.001; Vcf/LVEDVI,
r=-0.72,
P<0.001; and ESS/LVESVI,
r=-0.49,
P<0.001). Conversely, it was
positively correlated with ventricular systolic
volume (LVESVI, r=0.74,
P<0.001) and
diastolic volume (LVEDVI,
r=0.62,
P<0.001). The
multivariate stepwise analysis revealed that
ESS was the most predictive independent variable for Ang II
formation (r=0.85,
P<0.001)
(Table 3,
Figure 1B).
|
mRNA Expression of the Cardiac RAS
Components
RT-PCR Assay
AGTN, ACE, and chymase genes were expressed in the NF
hearts, whereas renin mRNA was not detectable
(Figure 2). AGTN and ACE mRNA levels were higher in failing
than in NF hearts, without any significant differences between ICM and
DCM hearts
(Figure 2). Conversely, chymase mRNA expression did not
significantly differ in failing and NF hearts
(Figure 2).
|
Messengers for AT1 and
AT2 were expressed in all myocardial specimens.
The AT1 mRNA levels were lower in failing than
in NF hearts (P<0.01)
(Figure 2).
In Situ Hybridization
Negative and positive controls for in situ
hybridization showed that the hybridization signal was specific for
mRNA and that the mRNA in the hearts was
intact).
In NF hearts, mRNA for AGTN and ACE was expressed only in trace
amounts. In the specimens from HF hearts, mRNA expression for AGTN and
ACE was notably enhanced and was expressed almost exclusively on
nonmyocyte cells
(Figure 3).
|
Immunohistochemical Localization of Ang
II
In NF hearts no immunostaining for Ang
II was detected. In HF hearts immunostaining for Ang II
was detected in both myocytes and interstitial cells
(Figure 3).
Ang II Binding in NF and Failing Hearts
The density, affinity, and relative proportion of
AT1 to AT2 subtypes in
membranes and isolated myocytes are reported in
Table 4.
|
In membranes from NF hearts, the proportion of
AT1 to AT2 subtypes was
62:38
(Table 4). Total Ang II receptor and
AT1 subtype densities were significantly reduced
in failing hearts as compared with NF hearts, with no significant
differences between ICM and DCM hearts
(Table 4).
Myocytes isolated from the left ventricle of NF hearts
showed a prevalence of the AT1 subtype
(AT1:AT2=79:21).
AT1 and AT2 density and
affinity were unchanged in myocytes from failing hearts as compared
with NF hearts
(Table 4).
Effects of Ang II Stimulation on PreproET-1
(ppET-1), IGF-I, and PDGF Synthesis
Ventricular cardiomyocytes from
NF hearts expressed very low levels of ppET-1, IGF-I, and PDGF mRNAs at
quiescent state
(Figure 4). Stimulation of myocytes with Ang II (10 nmol/L)
did not change GAPDH gene expression
(Figure 4) but induced a marked increase in ppET-1, IGF-I,
PDGF-A, and PDGF-B mRNAs
(Figure 4).
|
In cardiomyocytes from NF, ICM, or DCM hearts,
Ang II failed to induce ppET-1 and IGF-I gene expression, whereas
PDGF-B and PDGF-A gene expression was comparable among groups
(Figure 4).
The assay of big ET-1, IGF-I, and PDGF-AB in the conditioned
media from stimulated cardiomyocytes confirmed at the
peptide level the selective impairment of ET-1 and IGF-I response to
Ang II stimulation
(Figure 4).
Discussion
The major findings of this study may be summarized as follows: (1) the progression of HF is associated with a progressive increase in cardiac Ang II formation, regardless of the etiology of the HF and with a strong correlation with the increasing ESS; (2) the density and relative proportion of AT1 and AT2 on isolated HF myocytes are not significantly different from those on NF myocytes; and (3) Ang II stimulation does not induce HF myocytes to synthesize ET-1 and IGF-I.
Increased Ang II Formation and Cardiac
Function
Although the gene overexpression of ACE in dilated
cardiomyopathy was previously
reported,4 the finding of a
high aorta–coronary sinus concentration gradient of both
endogenous angiotensins and the kinetics study
of 125I-Ang I in the present work
demonstrate an increased cardiac Ang II formation in HF. Upregulation
of ACE and AGTN mRNAs and the immunohistochemical demonstration of Ang
II in failing hearts corroborate this finding. It is worth stressing
that the increased Ang II generation is independent of the HF etiology.
In failing hearts, Ang II was detectable at immunohistochemistry both
in myocytes and interstitial cells, whereas AGTN and ACE
mRNAs were expressed predominantly in nonmyocytes. These
findings may not be conflictual because in situ hybridization may be
unable to reveal a low increase in mRNA expression and Ang II is
uptaken by AT1 and via endocytosis rapidly
accumulated in myocytes.20
The enhanced Ang II generation is mainly due to the de novo Ang I
formation by cardiac tissues, despite the fact that RT-PCR did not
reveal any expression of renin mRNA in either the NF or the failing
hearts
(Figure 2). However, the presence of renin mRNA and its
overexpression in cardiac tissues from HF patients is not indispensable
for Ang I formation, because there is wide evidence that renin may be
uptaken from plasma by various renin binding
proteins21 22 23
and bound to subendothelium and
endothelial
cells.6 21 There
is also evidence that cardiac-bound renin may use the plasma AGTN
present in cardiac extracellular fluid in addition to locally
synthesized AGTN to generate Ang
II.6 Therefore, the finding
of increased cardiac Ang I does not in any way contradict the finding
that renin mRNA was not detectable in the HF hearts.
ACE mRNA levels in myocardium from failing hearts were higher than in NF hearts. In contrast, mRNA for chymase, a chymostatin-sensitive serine-proteinase,7 8 was expressed only in traces, without any significant differences between NF and failing hearts. Thus, the present results suggest that in failing hearts Ang II generation mainly occurs through an ACE-dependent pathway.
Cardiac renin and plasma renin have been found to be in a diffusional steady state in rats,24 and a positive correlation has been reported between renin plasma levels and the renin concentration in end-stage hearts from patients with DCM.6 In this study as well, cardiac Ang II formation was correlated with PRA values in patients with severe HF (NYHA classes III and IV; r=0.47, P<0.001) but not in those with mild HF (NYHA classes I and II; r=0.32, NS), the majority of whom had increased Ang II formation by cardiac tissues, although the PRA did not differ from that of control subjects. Likewise, multiple-regression analysis did not select PRA as a predictive independent variable for Ang II formation. These findings suggest that local cardiac factor(s) are preeminent in the activation of cardiac RAS in HF, even if important elevation in PRA contributes to the cardiac Ang II formation. Independently of the adjunctive role of PRA, the cardiac generation of both angiotensins progressively increases in relation with the impairment of cardiac function. The stepwise regression analysis revealed the ESS as the only variable independently correlated with Ang II formation (r=0.85). That the increase in ESS may play a major role in the upregulation of cardiac RAS is also supported by several studies that have shown that stretch induces Ang II formation both by isolated myocytes25 and by beating hearts.26 27 In patients with cardiac hypertrophy due to aortic valve disease, cardiac Ang II formation was again enhanced only in the patients with high ESS (>90 kdyn/cm2), regardless of the type of overload (pressure or volume).14 The close relationship between increased cardiac Ang II formation and high ESS values is not surprising, because ESS is a sensitive indicator of decompensation of dilated cardiomyopathy. Thus, clinical and experimental results suggest that ESS is a causative factor for the increase in Ang II formation in human hearts, probably stimulating the upregulation of both ACE and AGTN genes and facilitating the diffusion of renin from plasma to cardiac tissues. Cardiac Ang II production was negatively correlated with myocardial contractility as expressed not only by Vcf but also by the ESS/LVESVI ratio, which is a sensitive contractility index independent of ventricular size. However, ESS was the strongest predictor of Ang II production, thus indicating that a mechanical factor rather than the loss of contractility affects cardiac Ang II production.
Myocyte and Membrane Receptor Binding
Sites
Although the presence of AT1 was
demonstrated using in situ RT-PCR in both myocytes and
interstitial
cells,9 the density of Ang II
binding sites both in failing and NF hearts has been studied only on
cardiac homogenates. The results indicate a general
tendency of AT1 to decrease in failing hearts,
with no changes in
AT2.9 10
In contrast with these studies, Tsutsumi et
al11 reported that
AT2 binding sites and mRNA expression were
increased in patients with dilated cardiomyopathy.
In the present study, binding sites for Ang II receptors were
separately investigated in isolated myocytes and in myocardial
membranes. The results showed notable differences between myocytes and
membranes from NF hearts in the distribution and relative proportion of
the Ang II receptor subtypes. Ang II binding sites on myocytes from NF
hearts were 
10% of the binding sites detected on
ventricular membranes, with a clear predominance of
AT1s, which were 4 times more numerous than
AT2. Most importantly, whereas binding site
density for AT1 was lower on heart membranes
from failing than from NF hearts, the density of both
AT1 and AT2 on isolated
myocytes from HF hearts did not significantly differ from that of NF
hearts. Thus, for the first time we demonstrated that
AT1 density is decreased on cardiac membranes
but not on myocytes from failing hearts, and the myocytes may therefore
remain in end-stage failing hearts as potential targets for Ang
II–mediated effects. The downregulation of Ang II receptors on
nonmyocyte cells appears to be related to the HF and not to a
disease-specific mechanism, because no differences between DCM and ICM
hearts were found in the receptor density on either myocytes or
membranes. Thus, the pattern of Ang II receptors does differ from that
of ET-1 binding sites, which were increased in ICM hearts but not in
DCM ones, with a proportional increase in ETA
and ETB receptors both on myocytes and
membranes.19
The mechanisms responsible for the lack of downregulation of AT1 on myocytes in comparison with nonmyocyte cells, notwithstanding the increased Ang II, have not yet been clarified. Mechanical stretching increases AGTN mRNA levels and upregulates the number of AT1s and AT2s in neonatal cultured cardiac myocytes,28 29 30 and this effect is potentiated by Ang II.29 Moreover, Ang II levels were found to be directly related to AT1 promoter activity in pressure-overloaded myocytes.31 The combination of stretching and Ang II might thus keep the receptor density on failing heart myocytes similar to that of control subjects; conversely, the lower stretching effect on the nonmyocyte cells in comparison with myocytes might result in a predominance of the downregulating activity by the enhanced Ang II. Another possibility is that the different regulation of AT1 and AT2 may depend on differences in the regulation mechanism(s). Indeed, a different molecular mechanism has been found to regulate Ang II receptor subtype expression in the rat heart in a cell- and subtype-specific manner.32 A similar mechanism might differently regulate the gene expression of AT1 subtype on myocytes and on nonmyocyte cells. However, specifically addressed studies are needed to investigate the different expression of Ang II receptor subtypes in the failing human heart.
Incapacity of the Failing Myocytes to
Synthesize IGF-I and ET-1 and Role of Ang II in HF
The third major result in this study is the
demonstration that Ang II induces IGF-I, ET-1, and PDGF-AB synthesis by
human isolated NF myocytes and that failing myocytes are selectively
unable to produce appreciable amounts of IGF-I and ET-1 in response to
Ang II stimulation, notwithstanding the similar density and binding
capacity of Ang II receptor subtypes. The preserved PDGF-AB generation
by failing myocytes after Ang II stimulation suggests a specific
impairment of the pathways leading to IGF-I and ET-1 formation rather
than a general aspecific desensitization of the Ang II receptors. The
mechanisms responsible for the incapacity of failing myocytes to
produce IGF-I and ET-1 after Ang II stimulation remain to be
investigated. Multiple signal-transduction pathways are
activated in response to AT1
stimulation,33 and many
steps intervene between receptor activation and the molecular response
that increases myocyte IGF-I and ET-1 synthesis. Thus, the defective
response of failing myocytes to Ang II stimulation may reside either in
intracellular signal transduction pathways or in transcription factors.
Specific studies are, however, necessary to investigate this
problem.
Cardiac IGF-I and ET-1 play a critical role in supporting
cardiac adaptive response to hemodynamic overload.
Human compensatory hypertrophy due to aortic valve disease
is associated with an increased cardiac myocyte formation of IGF-I in
volume overload and IGF-I and ET-1 in pressure
overload.14 Cardiac
production of these growth factors is positively related to
myocardial
contractility.14
The depression of contractility, the increase in ESS,
and the progression toward noncompensatory hypertrophy and
HF are associated with the decrease in IGF-I and ET-1 myocyte formation
and with the increase in Ang II
generation.14 In
experimental pressure or volume overload in pigs, aortic banding or the
creation of an aorta-cava shunt are immediately followed by an
increased cardiac Ang II formation (within 3 hours), leading to
enhanced ET-1 and IGF-I generation by myocytes with recovery of
contractility, ESS normalization, and return of Ang II
formation to resting values within 12
hours.34 It is important to
highlight that Ang II, ET-1, and IGF-I are synthesized by myocytes, in
contrast with the incapacity of human
overloaded14 or failing
myocytes to synthesize not only ET-1 and IGF-I, but also Ang II itself,
which appears to be essentially formed by nonmyocyte cells
(Reference 1414 and the present study). Thus, the increased cardiac
Ang II formation triggered by the increase in the ESS operates as an
inducing factor for the formation of IGF-I and ET-1 (and perhaps other
growth factors) by myocytes. In noncompensatory hypertrophy
and HF, myocytes are unable to respond to the stimulating activity of
Ang II. Because AT1s on myocytes are not
downregulated in failing hearts, the long-lasting excessive Ang II
formation can mediate detrimental effects on overloaded or failing
myocytes, including depression of contractility or
impaired relaxation.35
AT1s also remain well represented on
fibroblasts from failing
hearts36 with consequent
interstitial extracellular matrix
accumulation.11 Moreover,
experimental evidence suggests that local Ang II through
AT1 activates the transcription factor
nuclear factor-
B,37
thereby promoting overexpression of numerous genes, including various
cytokines and adhesion
molecules.
In conclusion, the present study demonstrates that early in the clinical course of HF, cardiac Ang II formation is increased, myocyte AT1s are not downregulated, and myocytes are unable to synthesize IGF-I and ET-1 in response to Ang II stimulation.
Acknowledgments
The financial support of Telethon-Italy (Grant 864) and of the Ministero dell’Universitá e della Ricerca Scientifica (Project 9806103104) is gratefully acknowledged.
Footnotes
Original received January 30, 2001; revision received March 8, 2001; accepted March 9, 2001.
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