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© 1996 American Heart Association, Inc.
Articles |
Endothelium-Dependent and -Independent Vasodilation of Large Arteries in Normoalbuminuric Insulin-Dependent Diabetes Mellitus
From the Department of Internal Medicine, Academic Hospital and the Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, the Netherlands.
Correspondence to Dr J. Lambert, Department of Internal Medicine, Academic Hospital, Vrije Universiteit, PO Box 7057, 1007 MB Amsterdam, the Netherlands.
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Abstract |
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Abstract Vascular complications in diabetes mellitus are associated with endothelial dysfunction. Whether endothelium-dependent vasodilation is impaired in normoalbuminuric patients with insulin-dependent diabetes mellitus (IDDM) is controversial. Using a noninvasive echo-Doppler method, we investigated endothelium-dependent and endothelium-independent vasodilation in the brachial artery of IDDM patients. There were 52 normoalbuminuric and normotensive patients with IDDM (aged 31.9±9.8 years; diabetes duration, 14.9±7.9 years; glycated hemoglobin, 7.9±1.2%) and 52 healthy control group (C) subjects comparable for age and sex studied. Brachial artery diameter was measured at baseline, during postocclusion reactive hyperemia (flow-mediated, endothelium-dependent dilation [FMD]), and after 400 µg glyceryl trinitrate (GTN) sublingually (endothelium-independent vasodilation). Vasodilation was expressed as the percentage change relative to the baseline diameter. Baseline flow and blood pressure were similar for IDDM patients and C. Baseline vessel diameter was slightly larger in IDDM patients (3.10±0.52 mm) compared with C (2.89±0.55 mm, P=.05). FMD in IDDM patients was decreased (12.0±9.1% versus 15.7±9.5% in C, P=.046), as was GTN-induced vasodilation (14.9±8.2% versus 18.3±8.5% in C, P=.045). After correction for the difference in baseline diameter, FMD and GTN-induced dilation were not different between the groups. GTN-induced vasodilation decreased slightly with increasing diabetes duration. There was no relation between the vasodilatory responses and HbA1c. In normoalbuminuric IDDM patients, endothelium-dependent as well as endothelium-independent vasodilation are normal when the difference in baseline diameter is taken into account.
Key Words: endothelium-dependent vasodilation • diabetes mellitus • brachial artery diameter
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Introduction |
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Insulin-dependent diabetes mellitus is associated with microvascular and macrovascular complications. Atherosclerotic cardiovascular disease in IDDM is closely linked to the presence of microangiopathy, especially diabetic nephropathy.1 This association is already present at the early stage of diabetic nephropathy, ie, in patients with microalbuminuria.2 Endothelial function is abnormal in IDDM patients with (early) diabetic nephropathy (reviewed in References 1 and 31 3 ), which may explain their propensity to develop cardiovascular disease.
Endothelial dysfunction in microalbuminuric IDDM patients is generalized, in that it affects many aspects of endothelial function, such as the regulation of vascular resistance,4 vascular permeability,1 coagulation, and fibrinolysis.5 6 It is not clear, however, whether endothelial dysfunction is also present in IDDM patients with normal urinary albumin excretion, ie, whether in IDDM it is a feature of the diabetic state per se.
The endothelium produces vasoconstrictive and vasodilatory substances that regulate the vascular tone, as well as substances that influence platelet/vessel wall interactions and vascular smooth muscle cell growth.7 8 9 Recent studies have postulated a primary disturbance of endothelium-dependent vascular dilation as a causative mechanism of early atherosclerosis in IDDM,10 11 thus focusing attention on a possible deficit in the bioactivity of endothelium-derived relaxing factor/nitric oxide. However, several findings are in conflict with this hypothesis. First, early (uncomplicated) IDDM is accompanied by microvascular dilation, not constriction, and an increase in microvascular blood flow, both in humans and animal models.12 13 14 Second, studies in animals suggest that NO production in early diabetes may be increased rather than decreased.14 Studies in humans, using the response to intra-arterial infusion of cholinergic agents as an estimate of nitric oxide–mediated, endothelium-dependent vasodilation and the response to nitroprusside as a measure of endothelium-independent vasodilation, have produced conflicting results.4 10 11 15 16 Some investigators reported decreased endothelium-dependent vasodilation,11 but other studies showed endothelium-dependent and -independent vasodilation to be comparable with that in healthy control subjects.4 15 16 Postocclusion reactive hyperemia, a response that may also be NO mediated,17 18 has similarly been reported as diminished19 or normal.11 15 20 Thus, it is unclear whether NO-mediated vasodilation is diminished in uncomplicated IDDM. Some of the discrepancies among earlier studies may be explained by the small numbers of subjects investigated,4 10 11 15 16 19 20 failure to rigorously exclude microalbuminuric patients,10 11 and inclusion of patients with short-term IDDM only.10
It should be noted that previous studies have investigated endothelium-dependent vasodilation in resistance vessels.4 10 11 15 16 19 20 There are no data on endothelium-dependent vasodilation in conduit vessels, the type of vessel that is most prone to develop atherosclerotic lesions.
In view of these considerations, we wished to investigate endothelium-dependent and -independent vasodilation in conduit vessels in a large group of IDDM patients with normal urinary albumin excretion over a wide range of diabetes duration.
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Methods |
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Subjects
The protocol was approved by the local ethics committee, and all participants gave their informed consent. Fifty-two patients with IDDM and 52 healthy control subjects comparable for sex and age were studied. Characteristics of the groups are shown in Table 1
. The diabetics all had normal urinary albumin
excretion (albuminuria <30 mg/24 h; at least two
measurements), normal blood pressure (<160/95 mm Hg), and no clinical
signs of autonomic neuropathy. On funduscopic examination,
4 patients had proliferative diabetic retinopathy, 6
had background retinopathy, and 42 had no
retinopathy. In the control group, 12 women used oral
contraceptives compared with 11 in the diabetic group. Except for
insulin in the diabetic group (mean, 55±13.9 U/d), no subject took any
medication known to have a hemodynamic action.
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Hemodynamic Measurements
All subjects refrained from smoking and from use of
caffeine-containing beverages for at least 4 hours before the start
of the measurements. All measurements were done in the brachial artery
of the right arm, just above the elbow. We chose the brachial artery as
the conduit vessel of interest for two reasons. First, dilation of the
brachial artery can be directly and noninvasively assessed using
high-resolution ultrasound.21 22 23 24 25 Second, preliminary
data indicate that endothelial dysfunction in the
brachial artery parallels that in the coronary
artery.26
All measurements were done with a vessel wall–movement detector
system (Wall Track System, Neurodata), which consists of an ultrasound
imager (Ultramark IV, ATL) connected to a data acquisition and
processing unit. It is capable of measuring the brachial artery
diameter from the M-mode echos of the anterior and posterior vessel
walls with an accuracy of 
0.1 to 0.2 mm.27 Briefly, a
longitudinal section of the vessel is obtained in B-mode with a 7-MHz
transducer. When the M-mode is used, the vessel-movement detector
system repeatedly registers and averages the vessel wall distention and
diastolic D during a period of 5 to 6
seconds.27 In addition, PSV was measured by Doppler in
the center of the artery at a 60° angle to the vessel, with a range
gate of 1.5 mm.
We used an acute increase in blood flow, which increases shear stress on the endothelium, as the stimulus to elicit flow-mediated, endothelium-dependent vasodilation, according to a recently described procedure.21 22 23 24 25 The baseline diastolic D and PSV were measured after 15 minutes of supine rest. An increase in brachial artery blood flow was then induced by releasing a blood pressure tourniquet that had been inflated for 4 minutes at a pressure of 100 mm Hg above the systolic blood pressure. The maximum PSV during the first 15 seconds after releasing the tourniquet was recorded; D was measured between 45 and 60 seconds after the release of the cuff. After another 15 minutes of rest to allow the artery to return to its baseline diameter, D and PSV measurements were repeated before and 5 minutes after the administration of 400 µg GTN sublingually (to elicit endothelium-independent vasodilation).21 22 23 24 FMD and GTN-induced vasodilation were expressed as a percentage change relative to the baseline diameter. The change in PSV was expressed as a percentage of the baseline PSV.
The time points (after release of the cuff and after administration of GTN) of measurement of D were chosen on the basis of earlier reports,21 22 23 24 and their validity is supported by the following observations. In 10 healthy control subjects (8 men, 2 women; aged 28.3±5.0 years), D was measured as above and also 1.5, 2, and 3 minutes after deflating the cuff. The increase in D was maximal at 45 seconds and showed no further increase (1.5 minutes, 100.2±2.2%; 2 minutes, 100.6±2.8%; and 3 minutes, 103.0±6.9% of the FMD at 45 seconds). Similarly, D after GTN was maximal at 5 minutes and showed no further increase at 6, 7, or 8 minutes (6 minutes, 101.5±2.3%; 7 minutes, 99.4±2.5%; and 8 minutes, 100.5±1.8% of the GTN-induced vasodilation at 5 minutes). Therefore, FMD is stable and likely to be maximal from 45 seconds up to 3 minutes after reactive hyperemia, as is vasodilation from 5 minutes up to 8 minutes after GTN. The experiments were then repeated on a separate day. The reproducibilities of baseline D, FMD (measured at 45 seconds), and GTN-induced vasodilation (measured at 5 minutes) were 4.6%, 5.5%, and 7.7%, respectively.
It should be recognized that for two reasons we report the change in PSV, not the change in blood flow (which might be calculated from D and PSV), as a quantitative estimate of reactive hyperemia (ie, the stimulus that increases D). First, relating flow to D is problematic because flow is calculated from D and velocity and is therefore not independent of D.28 Second, because PSV is measured in the center of the vessel, the blood flow calculated from PSV and D overestimates the true flow.21
Because of suggestions in the literature of a larger baseline vessel diameter in IDDM14 and a similar tendency observed in an earlier, smaller study,29 we also measured the basal arterial diameter in the right common carotid artery, 10 mm proximal to the bifurcation.
Blood pressure and heart rate were measured on the left arm with an automated device (model BP-8800, Colin).
Laboratory Procedures
Glycated hemoglobin (HbA1c) was determined by
high-performance liquid chromatography
(Bio-Rad Laboratories BV). Serum cholesterol and
triglyceride levels were measured enzymatically by the
CHOD-PAP and the GPO-PAP methods, respectively (Boehringer
Mannheim). HDL cholesterol levels were determined after
precipitation of the VLDL and LDL with sodium
phosphotungstate/magnesium. LDL cholesterol was calculated
with the Friedewald formula.
Statistics
Data are expressed as mean±SD. Two-sample t
tests were used to compare diabetic patients and control subjects.
Univariate and multivariate regression
analyses were used to analyze the determinants of the
vascular responses. The multivariate analyses
were done after taking the IDDM patients and control subjects together
and adding a factor, "IDDM present or absent," to the model.
Only variables that were significantly (P<.05) related
to vascular responses in univariate analyses were
entered into the multivariate analyses. To
assess the influence on vascular responses of the diabetic state per
se, we repeated these analyses after exclusion of smokers and
patients with retinopathy. It should be emphasized that
FMD and GTN-induced vasodilation are conventionally reported as
percentage vasodilation, ie, (D+ 
D)/D.21 22 23 24 If in
regression analyses we wish to adjust for baseline D (which is
known to affect vascular responses28 ), we cannot use the
percentage vasodilation as the dependent variable, because relating
(D+ D)/D to D predictably yields a negative
relationship.30 We therefore used D after FMD and GTN (ie,
the absolute diameter) as the dependent variable in these
analyses.
Statistical significance was accepted at P<.05.
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Results |
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Hemodynamic results for both groups are shown in Table 2
. In two subjects, adequate postocclusion
diameters were not obtained (one in C and one in the diabetic group).
In four subjects, vascular diameters after GTN were unavailable due to
technical difficulties or refusal to take GTN (one control participant
and three diabetic patients). No adverse effects were seen apart from
slight palpitations, which were of short duration, after GTN in a few
cases. Systemic blood pressure did not change significantly during or
after FMD. The blood pressure decline, both systolic and
diastolic, after GTN was less than 10 mm Hg in all
participants.
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Baseline brachial D was slightly greater in the diabetic patients than
in C (3.10 mm in IDDM patients versus 2.89 mm in C, P=.05).
A similar difference was observed in the common carotid artery (6.31
[SD, 0.70] mm in IDDM patients versus 6.04 [SD, 0.43] mm in C,
P=.02). As shown in Fig 1, the FMD and
vasodilation after GTN (in the brachial artery) were both slightly less
in the diabetic patients than in C (FMD: 12.0% in IDDM patients and
15.7% in C, P=.046; GTN: 14.9% in IDDM patients and 18.3%
in C, P=.045). Hyperemia, assessed by the percentage
increase in PSV, was not different (236% in IDDM patients versus 227%
in C, P=.39). After exclusion of smokers and diabetic
patients with retinopathy, the results for baseline
diameter (3.03 [SD, 0.52] mm in IDDM patients versus 2.83 [SD,
0.54] mm in C, P=.12), FMD (12.9% [SD, 9.8%] in IDDM
patients versus 17.3% [SD, 9.9%], P=.07), and
GTN-induced vasodilation (14.3% [SD, 8.0%] in IDDM patients versus
17.7% [SD, 8.7%], P=.09) were essentially the same.
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Univariate analysis in the total group of
participants indicated that baseline D was the most important predictor
of vascular responses. In addition, baseline D differed between the
groups, being larger in IDDM patients (Table 2
). Fig 2
shows that when this difference is taken into account by relating D
after FMD and GTN to baseline D, FMD is normal in IDDM patients; the
response to GTN is slightly diminished at higher D. (Regression lines
for IDDM patients yielded FMD,
y=0.9+0.82x; GTN,
y=1.01+0.82x; and for C: FMD,
y=0.56+0.95x; GTN,
y=0.32+1.06x. It should be noted that by
definition, the regression equations are valid only over the ranges
actually observed.) The regression lines were similar after exclusion
of smokers and patients with retinopathy (data not
shown).
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Multiple stepwise regression analyses in the diabetic patients and C taken together confirmed these results. Baseline D was consistently the most important predictor of D after reactive hyperemia; the only other variable significantly related to the vessel response was height (partial regression coefficient [r]=.86, P<.001 and r=.10, P=.03, respectively). Similarly, baseline D and height were significant predictors of D after GTN (r=.87, P<.0001 and r=.13, P=.003, respectively). Sex, age, weight, smoking, mean arterial blood pressure, HDL cholesterol, LDL cholesterol, triglycerides, and the presence of IDDM did not significantly influence either FMD or GTN-induced vasodilation. Additional analyses in small models that focused on the influence of smoking, sex, and lipid levels did not change the results (data not shown). Stepwise multiple regression analysis in the group of IDDM patients showed that diabetes duration was significantly related to D after GTN (r=-.21, P=.001) but not to D after FMD. Glycemic control (as estimated by measurement of HbA1c), sex, smoking, retinopathy, and lipid levels were not significantly related to the vascular response to FMD or GTN.
In the diabetic patients, baseline D was determined by weight, age, male sex, and glycemic control (explained variance of the model [adjusted R2]: .44; partial regression coefficients r=.30, P=.012; r=.29, P=.011; r=.31, P=.10; and r=.29, P=.10, respectively). There was no relation with diabetes duration.
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Discussion |
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This study is the first to show that IDDM patients with normal urinary albumin excretion tend to have a slightly larger brachial artery diameter than do healthy control subjects and that regardless of diabetes duration, FMD in the brachial artery is normal when this difference in arterial diameter is taken into account.
We chose not to include microalbuminuric patients because we wished to investigate whether decreased FMD precedes the occurrence of vascular complications of diabetes mellitus, ie, whether impaired endothelium-dependent vasodilation is present in IDDM per se. To avoid confounding, it is important to include patients without clinical evidence of vascular disease, as is done in other studies investigating patients at risk for premature atherosclerosis, eg, those with hypercholesterolemia.31 32 We therefore focused on normoalbuminuric patients, as have other authors,4 15 16 especially because this is the main area of disagreement among previously published studies and also because endothelial dysfunction has been convincingly demonstrated in microalbuminuric (as well as macroalbuminuric) patients.1 3 4 5 6 The method we have used has been shown to be able to demonstrate an impaired endothelium-dependent vasodilation in persons with other known risk factors for cardiovascular disease, such as hypercholesterolemia.22 23 24
An increase in blood flow stimulates endothelium-dependent vasodilation by increasing shear stress on the endothelium, both in conduit and resistance vessels.28 33 34 35 36 The vasodilation is to a large extent NO mediated17 18 37 38 39 40 and decreases the vascular wall shear stress, which is thereby maintained within physiological values.41 FMD as measured in this study is thought to provide an estimate of this response.21 In the investigation of the vascular effects of risk factors for atherosclerosis, the significance of measuring FMD is that it reflects the capacity of the vascular endothelium to normalize an increase in shear stress, thereby counteracting its atherogenic consequences.42 43 44 A clear reduction (to less than half of normal) of the brachial artery FMD has been observed in smokers,23 in patients with hypercholesterolemia,21 22 and in patients with atherosclerosis.21 Atherogenic risk factors (and the presence of atherosclerosis) are also associated with a reduced endothelium-dependent vasodilation in response to cholinergic agonists, both in the resistance vessels of the forearm and in the conduit and resistance vessels of the coronary circulation.26 45 46 47 Thus, endothelial dysfunction as measured by FMD in the brachial artery tends to parallel endothelial dysfunction in other parts of the vasculature, even if assessed with different methods.
Flow-Mediated Vasodilation and IDDM
Our finding of a normal FMD in IDDM patients with normal urinary
albumin excretion is consistent with several
observations. First, epidemiological studies indicate that the excess
risk of cardiovascular disease in IDDM is largely
confined to patients with microalbuminuria and overt
diabetic nephropathy.1 2 3 In addition, less
than 50% of IDDM patients will ever develop
nephropathy.1 These findings have led to the
hypothesis that hyperglycemia per se is necessary, but not sufficient,
to cause severe microangiopathy and atherosclerosis in
IDDM.1 48 This notion is supported by our present
observation of preserved endothelial function,
regardless of diabetes duration, provided the urinary albumin
excretion is normal. Recent data indicate that large-artery
compliance and distensibility are also normal in such
patients.29 Second, when studied under conditions of
moderate hyperglycemia, microcirculatory blood flow is typically
increased in uncomplicated IDDM, not only in target organs such as the
retina and kidney but also in the skin, forearm, and central nervous
system, and is accompanied by microvascular
dilation.3 13 14 16 49 When the baseline increase in blood
flow is taken into account, maximal skin microcirculatory vasodilation
is normal in IDDM patients with normal urinary albumin
excretion but not in microalbuminuric IDDM
patients.49 Third, studies that specifically excluded
microalbuminuric patients reported normal
endothelium-dependent vasodilation of forearm
resistance vessels in response to cholinergic
agonists4 15 16 and
ischemia.15 20
Johnstone et al,11 however, observed an impaired vasodilator response to methacholine in the forearm and concluded that NO synthesis and action are abnormal in IDDM. This study did not exclude microalbuminuric patients, however, and the results cannot be extrapolated to IDDM patients with normal urinary albumin excretion.50 In addition, the patients in their study had been pretreated with the cyclooxygenase inhibitor aspirin. Elliott et al4 have suggested that cholinergic vasodilation in microalbuminuric patients, although quantitatively normal, may be mediated by vasodilator prostanoids rather than by NO. If some of the patients in the study of Johnstone et al did in fact have microalbuminuria, the impaired response to methacholine might be explained by the aspirin pretreatment, which would impair any methacholine-induced effect on vasodilator prostanoids.
Most studies in humans, therefore, are consistent with the hypothesis that endothelium-dependent vasodilation is normal in IDDM patients with normal urinary albumin excretion. This conclusion cannot be extended to patients with non–insulin-dependent diabetes,51 however, in whom hyperglycemia tends to be accompanied by other risk factors, such as dyslipidemia, high blood pressure, and insulin resistance. In addition, our patients were reasonably well controlled, so that our results may not be valid for patients in poor glycemic control. In fact, Jorgensen et al20 observed a reduced vasodilatory response of forearm resistance vessels to reactive hyperemia only in poorly controlled IDDM patients.
GTN-Induced Vasodilation
Because GTN was systemically administered, whereas most other
studies infused an NO donor locally, our results should be interpreted
with caution. Nevertheless, other authors have also observed a normal
response to NO donors.4 11 15 However, Calver et
al10 observed a decreased response to sodium
nitroprusside, suggesting a defect at the level of the vascular smooth
muscle cell. In the study by Halkin et al,16 sodium
nitroprusside–induced vasodilation was normal but correlated
inversely with erythrocyte Na+-Li+
countertransport activity, a putative marker for the development of
complications in IDDM. In addition, we found a slightly decreased
vasodilation to GTN with increasing diabetes duration. Although these
discrepancies require clarification, our results suggest that there is
at most a very small decrease in
endothelium-independent vasodilation in IDDM
patients with normal urinary albumin excretion.
Baseline Vessel Diameter
Our study shows that conduit vessels (the brachial and common
carotid arteries), like resistance vessels, tend to be dilated in
uncomplicated IDDM. Baseline brachial arterial diameter was
an important determinant of FMD and GTN-induced vasodilation and should
therefore be taken into account when analyzing the effects of
atherogenic risk factors on these vascular responses. In addition,
conduit vessel dilation in IDDM may contribute to an increase in
microvascular blood flow, which increases capillary
pressure,12 13 14 an important factor in the pathogenesis of
diabetic microangiopathy.
Although it is generally agreed that vasodilation is a prominent feature of early IDDM, the responsible mediators have not been identified. Williamson et al14 have argued that vasodilation in IDDM resembles that in response to tissue hypoxia and that both are characterized by an increased intracellular NADH/NAD+ ratio. In IDDM, the latter may alter various interrelated biochemical pathways, resulting in altered cellular signal transduction (eg, increases in 1,2-diacyl-sn-glycerol and protein kinase C activity) and production of vasoactive mediators (eg, increases in prostanoids and NO). Thus, in several animal models of IDDM, vasodilation was shown to be related to an increase in the synthesis and action of NO.14 52 Under certain circumstances, however, experimental diabetes or hyperglycemia appeared to be associated with a decrease in endothelium-dependent vasodilation.53 54 55 56 At present, there is no clear evidence in favor of either of these hypotheses in human IDDM. As discussed, most studies in uncomplicated IDDM in humans, including ours, suggest that endothelium-dependent vasodilation in response to cholinergic agonists or increased flow is neither enhanced nor impaired.4 10 15 16 In contrast, the response of forearm resistance vessels to infusion of NG-monomethyl-L-arginine, an inhibitor of basal NO synthesis, has been reported to be diminished,4 10 suggesting a decrease in basal NO synthesis and/or action. Given the basal vasodilation of IDDM, however, it is difficult to conclude that this represents endothelial dysfunction. Another possible mechanism of vasodilation in IDDM is an increased production of vasodilator prostanoids, at least in the kidney. Whether they mediate renal or conduit vessel vasodilation in human IDDM is not clear, however (reviewed in Reference 33 ). Finally, other possibilities need to be considered, such as a decrease in the secretion of the potent vasoconstrictor endothelin57 and the vasodilator effects of hyperinsulinemia,58 which is typical of IDDM treated with subcutaneous insulin.
Study Limitations
Our study has several limitations. First, we have not directly
shown that FMD was NO mediated. Other
endothelium-derived vasoactive mediators may play a
role in certain experimental conditions,59 60 and we
cannot exclude that this may also be the case in our patients.
Nevertheless, this does not detract from our finding that FMD was
quantitatively normal in IDDM patients with normal urinary
albumin excretion. Second, FMD, although reproducible within a
person, is quite variable among healthy
volunteers21 22 23 24 (Fig 1). Our data, therefore, have limited
power to exclude the possibility that patients with a low response to
FMD belong to a subgroup of IDDM patients at increased risk of
developing microalbuminuria and atherosclerotic
disease, which has been suggested by epidemiological1 3
and family48 studies and supported by our recent
observation that persistent increases in the plasma concentration of
von Willebrand factor, a marker of endothelial
injury, precede the development of microalbuminuria by
about 3 years.61 Finally, whether
microalbuminuric IDDM patients have impaired
FMD62 also needs further investigation.
Conclusions
Our results show that endothelium-dependent
and -independent vasodilation in the brachial artery of IDDM patients
with normal urinary albumin excretion is not different from
healthy control subjects. These findings are consistent with
epidemiological data indicating that the increased risk of
atherosclerotic cardiovascular disease in IDDM is
mainly confined to patients with abnormal urinary albumin
excretion, ie, microalbuminuria or overt diabetic
nephropathy.1 3
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant from the Diabetes Fonds Nederland (Diabetes Research Fund). Dr Stehouwer is supported by a Clinical Research Fellowship from the Diabetes Fonds Nederland and the Netherlands Organization for Scientific Research (NWO). We thank W. Devillé for statistical assistance and Servier Netherlands for financial support of the Wall Track System.
Received July 26, 1995; accepted January 18, 1996.
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