Vol. 274, Issue 5, C1298-C1305, May 1998
Structure and in vitro function of human subcutaneous small
arteries in mild heart failure
Nicola
Stephens1,
Mark J.
Drinkhill2,
Alistair S.
Hall2,
Stephen G.
Ball2, and
Anthony M.
Heagerty1
1 Department of Medicine,
Manchester Royal Infirmary, Manchester M13 9WL; and
2 Institute for Cardiovascular
Research, University of Leeds, Leeds LS2 9JT, United Kingdom
 |
ABSTRACT |
The structure and function of subcutaneous small arteries from
patients with mild heart failure
(n = 27) 6-43 mo after
myocardial infarction were compared with vessels from healthy control
subjects (n = 10). Patients were
randomized to treatment with placebo or the angiotensin-converting
enzyme inhibitor ramipril starting 3-10 days after myocardial
infarction. Dissected arterial vessels were mounted on a wire myograph
for measurement of morphology and isometric tension. Morphology was not
different in arteries from the three groups. Responses to
norepinephrine, angiotensin II, and electrical field stimulation were
similar in arteries from placebo-treated patients with mild heart
failure and control subjects. Similarly, endothelium-dependent and
-independent relaxation was normal in arteries from patients with mild
heart failure. Ramipril therapy was associated with functional
alterations: vasoconstrictor responses to norepinephrine and
angiotensin II were significantly enhanced compared with placebo
(P < 0.001). These data suggest that
vascular structure and function are not different in vitro in
subcutaneous arteries from placebo-treated patients with mild heart
failure. Angiotensin-converting enzyme inhibitor therapy is associated
with enhanced vasoconstriction to norepinephrine and angiotensin II,
which may reflect upregulation of receptor-mediated events.
angiotensin-converting enzyme inhibitor; ramipril
| |
INTRODUCTION |
THE PREVALENCE OF HEART failure in the population is
between 1 and 3%, carrying with it a particularly poor prognosis.
Although the primary abnormality is loss of functioning myocardium, the resulting fall in cardiac output leads to an activation of a number of
compensatory neuroendocrine mechanisms, such as the sympathetic nervous
and renin-angiotensin systems (8, 30, 36, 37). To maintain blood
pressure, these mechanisms produce inotropic stimulation of the
residual myocardium, peripheral vasoconstriction, and fluid retention.
Although in the short term cardiac output is improved, over a longer
period direct cardiotoxic effects of angiotensin II and norepinephrine
and an increase in peripheral vascular resistance contribute to the
progressive decline in cardiac function.
The role of the peripheral vasculature in this process is not clear. In
theory, high concentrations of catecholamines and plasma renin (18, 25,
32, 41), through the formation of angiotensin II, could influence the
function of small blood vessels, and also there are reports that the
disease process itself is associated with impairment of
endothelium-dependent relaxation (5, 11, 26, 28). In addition, there is
the possibility that sympathomimetic amines and angiotensin II could
cause structural changes in the vasculature similar to those seen in
hypertensive subjects. Indeed, a study of patients with heart failure
with low-to-normal blood pressure might help resolve the debate over the importance of pressure per se or trophic hormone influence as major
determinants of small vessel hypertrophy.
In vitro investigation of the properties of peripheral resistance
arteries in heart failure has been limited to one study of a small
group of patients receiving a variety of medications (5). Therefore, we
decided to examine the structure and function of isolated, peripheral
small arteries from patients treated for heart failure after myocardial
infarction. It was possible to perform this study on a subpopulation of
patients randomized to placebo or the angiotensin-converting enzyme
(ACE) inhibitor ramipril, in addition to conventional therapy for heart
failure, thereby allowing an analysis of the effects of this class of
drug on small artery structure and function in this clinical situation.
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METHODS |
Patients and Control Subjects
Twenty-seven patients with clinically diagnosed congestive heart
failure (Killip classes II and III), after an acute myocardial infarction, were studied. The patients were a subset of those recruited
at Leeds, UK, as part of the Acute Infarction Ramipril Efficacy (AIRE)
Study (3), and all patients displayed clinical evidence of heart
failure, which was defined as at least one of the following: evidence
of left ventricular failure, evidence of pulmonary edema, or
auscultatory evidence of a third heart sound with persistent
tachycardia (3). In accordance with the AIRE Study entry criteria,
patients with severe heart failure (New York Heart Association
classification grade IV) had been excluded from the study. Patients
were randomly assigned to therapy with placebo or ramipril (2.5-5
mg twice daily) starting 3-10 days after myocardial infarction.
The mean duration of treatment was 27 ± 2 mo (range 6-43 mo).
Standard therapy was maintained for all patients throughout the trial,
and concomitant medications are indicated in Table
1. Subcutaneous skin biopsies were
performed on patients at the close of the trial (see below). At this
time, 24 of the 27 patients studied had a history of overt congestive heart failure that required treatment with diuretics or inotropic drugs
and/or vasodilators for symptomatic relief, fulfilling the Studies of Left Ventricular Dysfunction (SOLVD) criteria for congestive heart failure (39). Three of the patients fulfilled the SOLVD criteria
for asymptomatic left ventricular dysfunction. All patients had
evidence of reduced left ventricular function on the basis of
radionuclide scanning (method B) (24) at the time of biopsy. Ten
healthy volunteers from the general public were studied as control
subjects. They had no medical history of cardiovascular disease or
clinical evidence of heart failure or other cardiac pathology. All
patients/subjects gave informed, written consent to participate in the
study, and the protocol was approved by the local ethics committee.
Biopsy Procedure and Artery Preparation
By use of the method described previously (1, 2), gluteal skin biopsies
were obtained under local anesthetic (2% lignocaine) and placed in
cold physiological salt solution (PSS, see Drugs and
Solutions). Drug therapy was withheld for 24 h before
the biopsy was performed. Subcutaneous small arteries (~250 µm ID, 2-mm segment length) were dissected from the biopsy, cleaned of adherent fat and connective tissue, and mounted on a wire myograph (JP
Trading, Aarhus, Denmark) for measurement of morphology and isometric
tension (22). In most cases, two vessels from each biopsy were studied.
Myograph-mounted vessels were incubated in PSS, warmed to 37°C,
gassed with oxygen containing 5% carbon dioxide, and allowed to
equilibrate for 
30 min.
Experimental Protocol
Artery wall morphology was measured using a ×40 magnification
saline immersion lens (Zeiss), as described previously (35). The
resting tension-internal circumference relation was then determined for
each artery. Vessels were set to a normalized internal circumference of
0.9L100, where
L100 is the
internal circumference of the vessel under a transmural pressure of 100 mmHg (35). Effective normalized luminal diameters
(lo) were
calculated as
0.9L100/
.
In a standard start procedure, arteries were activated with 5 µmol/l
norepinephrine on three occasions, each for a period of 2 min with a
5-min washout between activations. Contraction elicited by
norepinephrine was expressed as effective active pressure (
P) on the
basis of the law of Laplace, where P = 2T/lo and T
is the change in tension. Arteries unable to produce an effective active pressure >12 kPa were considered unviable and were not used in
further analysis. With use of this criterion, 8 of a total of 66 arteries were rejected spanning the subject/patient groups. Cumulative
concentration-response curves were performed to the vasoconstrictor
agonists norepinephrine (0.01-10 µmol/l), in the absence and
presence of cocaine (3 µmol/l) and angiotensin II (0.0001-1
µmol/l) and to the vasodilator agonists acetylcholine (0.001-10
µmol/l) and sodium nitroprusside (0.001-10 µmol/l) after preconstriction with 5 µmol/l norepinephrine. Vessels were stimulated for 2 min at each concentration of a drug. Concentration-response curves were separated by a 20-min period, during which time arteries were incubated in PSS or, where appropriate, cocaine. The order in
which the concentration-response curves were performed was randomized.
Finally, a frequency-response curve to electrical field stimulation was
performed to determine the sensitivity to endogenous neurotransmitter
released from intramural sympathetic nerves. Arteries were incubated in
PSS throughout the stimulation. Platinum foil electrodes were secured
in the plastic myograph mounting heads and connected to an electrical
stimulator (Harvard Apparatus, Kent, UK), as described previously (40).
Arteries were stimulated at 20 V, 0.2-ms pulse width, 20-s pulse train,
with a 5-min interval between trains, over a frequency range of
1-24 Hz. Previous experiments indicate that vasoconstriction
elicited in this manner is sensitive to the nerve toxin tetrodotoxin
and is mediated via 
1- and
2-adrenergic receptors (40).
Data Analysis
Values are means ± SE; n refers to
the number of biopsies studied. Where two artery segments were studied
from a biopsy, the data from the vessels were averaged to provide a
single value per biopsy. Concentration- and frequency-response curves
were analyzed by repeated-measures ANOVA. This analysis was carried out
on the raw data by the method of maximum likelihood using the GLIM 3-77 package (4), and the adequacy of these analyses was determined by
constructing normal probability plots in conjunction with the Filliben
correlation coefficient (14). Tukey's multiple comparison test (44)
was used to determine differences between the three subject/patient
groups (control, placebo, ramipril) and the effect of cocaine on
norepinephrine sensitivity. Norepinephrine pD2 values were calculated as
log ED50, where
ED50 was the agonist concentration
required to elicit half-maximum contraction. One-way ANOVA followed by
Dunnett's test for multiple comparisons was used to compare
demographic, morphological, maximum response, and
pD2 values between control
subjects and heart failure patients treated with placebo and between
patients treated with ramipril and placebo. Statistical significance
was set at the conventional 5% level.
Drugs and Solutions
PSS had the following composition (mmol/l): 119 NaCl, 4.7 KCl, 2.5 CaCl2, 1.17 MgSO4, 1.18 KH2PO4,
0.026 K2EDTA, and 5.5 D-glucose. (±)-Norepinephrine hydrochloride, acetylcholine hydrochloride, human angiotensin II, cocaine hydrochloride, and sodium nitroprusside were obtained from Sigma Chemical.
| |
RESULTS |
Demographic Data
Demographic details, taken at the time of biopsy, of control subjects
and heart failure patients treated with placebo or ramipril are shown
in Table 2. There was no significant
difference in the age of subjects or patients in the three groups.
Predictably, systolic blood pressure was significantly higher in
control subjects than in heart failure patients treated with placebo
(P < 0.001). Systolic blood pressure
was also higher in patients treated with placebo than in those treated
with ramipril, but the difference was not statistically significant.
Diastolic blood pressure was similar in control subjects and patients
treated with placebo but was significantly lower in patients treated
with ramipril than in patients treated with placebo
(P < 0.001). Left ventricular ejection fraction (LVEF) was 47 ± 3% for patients treated with placebo and 41 ± 4% for patients treated with ramipril; there was
no significant difference between the two treatment groups.
Morphology
The morphology data for arteries from each of the subject/patient
groups are shown in Table 3. One-way ANOVA
failed to reveal significant differences among the three groups for
normalized luminal diameter, media thickness, media-to-lumen ratio, or
media cross-sectional area. Therefore, there were no significant
differences in any parameter between arteries from control subjects and
patients receiving placebo. However, luminal diameter tended to be
greater and media-to-lumen ratio tended to be less in arteries from
ramipril-treated patients than in patients treated with placebo. A
multiple comparison test (Tukey) between the ramipril-treated group and
the placebo and control groups combined demonstrated that the
media-to-lumen ratio was significantly reduced in arteries from
patients receiving ramipril (P < 0.05).
Vasoconstrictor Responses
Angiotensin II elicited vasoconstriction, which was similar in arteries
from control subjects and heart failure patients treated with placebo
but was significantly enhanced in patients treated with ramipril (Fig.
1;
P < 0.001).
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Fig. 1.
Concentration-response curves to angiotensin II in arteries from
control subjects ( , n = 9) and
heart failure patients treated with placebo ( ,
n = 14) or ramipril ( ,
n = 12). Responses (means ± SE)
are expressed as percentage of maximum response to norepinephrine.
Contraction to angiotensin II was similar in vessels from control
subjects and patients treated with placebo but was significantly
increased in arteries from patients treated with ramipril
(P < 0.001).
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The maximum response to norepinephrine (5 µM), expressed as effective
active pressure, was similar in arteries from control subjects (21 ± 4 kPa) and patients treated with placebo (20 ± 2 kPa) or
ramipril (21 ± 2 kPa). The sensitivity to norepinephrine was
similar in arteries from control subjects and patients treated with
placebo but was significantly enhanced in patients treated with
ramipril (Fig. 2;
P < 0.001). Norepinephrine
pD2 values are given in Table
4. Incubation of arteries with cocaine, to
block neuronal amine uptake, significantly increased sensitivity to norepinephrine overall (P < 0.001);
the effect of cocaine was similar in all subject/patient groups (Table
4).
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Fig. 2.
Concentration-response curves to norepinephrine in arteries from
control subjects (, n = 9) and
patients treated with placebo (, n = 14) or ramipril (, n = 12).
Responses (means ± SE) are expressed as percentage of maximum
response to norepinephrine. Sensitivity to norepinephrine was similar
in arteries from control subjects and patients treated with placebo but
was significantly increased in arteries from patients treated with
ramipril (P < 0.001).
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The maximum response to electrical field stimulation (25 Hz), expressed
as effective active pressure, was not significantly different in
arteries from control subjects (6.0 ± 0.9 kPa) and patients treated
with placebo (4.5 ± 0.6 kPa) but was significantly greater in
arteries from patients treated with ramipril (7.0 ± 0.8 kPa) than
in placebo-treated patients (P < 0.05). Frequencyresponse curves to electrical field stimulation are
shown in Fig. 3. The sensitivity to
electrical field stimulation was not significantly different in
arteries from control subjects or heart failure patients treated with
placebo or ramipril (Fig. 3).
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Fig. 3.
Frequency-response curve to electrical field stimulation in arteries
from control subjects (, n = 8) and
patients treated with placebo (, n = 13) or ramipril (, n = 11).
Responses (means ± SE) are expressed as percentage of maximum
response to field stimulation. Responses to electrical field
stimulation were similar in arteries from all 3 groups.
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Vasodilator Responses
Repeated-measures ANOVA failed to reveal a significant difference in
acetylcholine-induced relaxation in arteries from the three
subject/patient groups (Fig. 4). However,
examination of the 95% confidence limits shows a significant
difference between arteries from patients treated with ramipril and
arteries from patients treated with placebo at the three highest
acetylcholine concentrations (1, 3, and 10 µmol/l,
P < 0.05). Relaxation to sodium
nitroprusside was not significantly different in arteries from the
three subject/patient groups (Fig. 5).
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Fig. 4.
Concentration-response curves to acetylcholine in arteries from control
subjects (, n = 9) and patients
treated with placebo (, n = 14) or
ramipril (, n = 12). Responses
(means ± SE) are expressed as percentage of norepinephrine-induced
preconstriction. Acetylcholine-induced relaxation in arteries from
control subjects was not significantly different from that in
placebo-treated patients but was significantly reduced in arteries from
patients treated with ramipril compared with those treated with placebo
at the 3 highest concentrations (P < 0.05).
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Fig. 5.
Concentration-response curves to sodium nitroprusside in arteries from
control subjects (, n = 9) and
patients treated with placebo (, n = 14) or ramipril (, n = 12).
Responses (means ± SE) are expressed as percentage of
norepinephrine-induced preconstriction. There was no significant
difference in relaxation induced by sodium nitroprusside in arteries
from the 3 groups.
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DISCUSSION |
In the present study we examined isolated segments of subcutaneous
small arteries from patients with clinical evidence of heart failure
after acute myocardial infarction treated with the ACE inhibitor
ramipril or placebo and matched healthy control subjects. Patients had
been recruited as part of the AIRE Study (3) and met the AIRE Study
criteria for diagnosis of heart failure after myocardial infarction.
Patients with severe heart failure (New York Heart Association
classification grade IV) were excluded from the study, restricting the
scope of this investigation to mild heart failure. At the time of
investigation (6-43 mo after myocardial infarction) the patients
displayed symptomatic mild heart failure on the basis of the SOLVD
criteria (39) and demonstrated impaired left ventricular function on
the basis of radionuclide scanning. The results suggest that there is
little alteration in vascular structure, contraction, or relaxation in
subcutaneous small arteries from patients with mild-to-moderate heart
failure who were treated with placebo. However, ACE inhibitor therapy tended to modify vascular structure and significantly influenced vascular function in subcutaneous arteries obtained from patients with
mild heart failure.
There were no significant differences in vascular morphology between
subcutaneous small arteries from mild heart failure patients and those
from healthy control subjects. However, normalized luminal diameter
tended to be increased and media-to-lumen ratio decreased in arteries
from patients receiving ramipril therapy compared with placebo. These
differences may indicate an influence of ACE inhibitors on vascular
structure. The cross-sectional area of media, which is an index of the
amount of smooth muscle, was not reduced in arteries from patients
receiving ramipril. Therefore, such vascular alterations may represent
a rearrangement of preexisting smooth muscle around a larger lumen,
i.e., "reverse remodeling" (19), or an increase in the elasticity
of the vessels so that a given transmural pressure is able to distend
arteries to a greater diameter. Evidence in the literature suggests
that ACE inhibitors increase vascular compliance (10, 16, 33, 38, 42),
offering a possible explanation for the apparent increase in luminal
diameter and reduction in media-to-lumen ratio in arteries from
patients treated with ramipril.
We observed little difference in the function of subcutaneous small
arteries between placebo-treated patients with mild heart failure and
control subjects. Responses to norepinephrine, angiotensin II, and
electrical field stimulation were not significantly different in terms
of maximum contraction and sensitivity in arteries from these two
groups. These data suggest little alteration in the vascular
contraction of subcutaneous small arteries in response to exogenous
agonists or endogenously released neurotransmitter in patients with
clinical evidence of mild heart failure treated with placebo. Our
findings contrast with those of another study (5), in which
subcutaneous arteries from six patients with longstanding (5-10
yr) and more severe heart failure (28 ± 6% LVEF), whose treatment
included ACE inhibitors, were studied. In the earlier study the maximum
contractility to a number of constrictor stimuli, including
norepinephrine and angiotensin II, was significantly reduced in
arteries from the patients (5). This was considered by the authors to
be a nonspecific "fatiguing" of the vascular smooth muscle (5).
The difference in findings may reflect the longstanding and more severe
nature of the disease in the patients studied by Angus and colleagues
(5) than in our patients with milder disease. However, although the
present study differed from that of Angus and colleagues, in that we
were able to distinguish between patients receiving ACE inhibitors and
those who were not, neither study provides any evidence for reduced
vascular smooth muscle sensitivity to norepinephrine or angiotensin II
in arteries from patients with mild or more severe heart failure.
The vasoconstrictor response to angiotensin II and norepinephrine was
augmented in subcutaneous small arteries from patients treated with
ramipril, possibly reflecting upregulation of receptor-mediated events
in response to decreased concentrations of these hormones at the level
of the receptor. Measurement of plasma angiotensin II indicates that
circulating levels are reduced as a consequence of ACE inhibitor
therapy, although not necessarily throughout 24 h, depending on dosing
schedule and dose and type (long or short acting) of agent (34).
However, if this were correct, one might expect downregulation by
higher levels of angiotensin II in patients with congestive heart
failure treated with placebo than in control subjects, which we did not
observe. In addition, there is evidence to suggest that ACE inhibitors
reduce levels of plasma norepinephrine (6, 15, 43). This may result
from a diminished stimulation of presynaptic angiotensin II receptors at sympathetic neuroeffector junctions, which normally serve to facilitate norepinephrine overflow (29). In addition, ACE inhibitors may reduce plasma norepinephrine by other effects, such as improved central hemodynamics, central nervous system effects, and lowering of
sympathetic outflow. Therefore, the increased vasoconstrictor response
to angiotensin II and norepinephrine after ACE inhibitor therapy may
reflect an interaction between the two systems, possibly at the
neuroeffector junction. Although the sensitivity to electrical field
stimulation was not significantly different in arteries from control
subjects and patients with mild heart failure in either treatment
group, the magnitude of the response to nerve stimulation was increased
in arteries from patients receiving ramipril compared with placebo,
which may also reflect an upregulation of the postjunctional response
to norepinephrine.
In the present study, subcutaneous small arteries from placebo-treated
patients with mild heart failure demonstrated normal endothelium-dependent and independent relaxation. Again,
these findings were in contrast to those from patients with
longstanding and more severe heart failure, in which
endothelium-dependent relaxation was markedly impaired in isolated
subcutaneous arteries obtained from the same region (5). Furthermore,
in vivo studies in patients with heart failure (mean LVEF <30%)
suggest that agonist-induced, endothelium-dependent vasodilation is
impaired in the forearm (11, 15) and femoral (14, 38) circulations, and
these impairments could not be attributed to altered plasma lipids or other risk factors. However, the response to dilators that act directly
on vascular smooth muscle (endothelium independent) is also impaired in
heart failure (21, 23, 26, 27, 31), so dysfunction may reside in part
with the vascular smooth muscle itself. Thus the impairment of dilator
function may reflect the severity of the disease; although relaxation
is impaired in patients with severe or longstanding heart failure, it
is not readily apparent in our patients with milder disease. In this
respect, the present data may support a previous observation that
dilator function was preserved in a subgroup of patients with
significantly higher LVEF (26).
Although endothelium-dependent relaxation was not impaired in
subcutaneous arteries from patients with mild heart failure treated
with placebo, ramipril therapy was associated with a slight reduction
in maximum relaxation compared with arteries from placebo-treated patients. The reason for this is unclear, particularly in view of
reports which suggest that ACE inhibitors improve endothelium-dependent relaxation in animal models of hypertension (7, 22) and essential hypertension (20), where endothelial function is abnormal in the first
instance. However, ACE inhibitors had no effect on
endothelium-dependent relaxation in control animals, which demonstrated
normal relaxation. Thus the reason for a slight reduction in relaxation
in subcutaneous arteries from patients treated with ramipril remains to
be resolved.
Limitations of the Study
Methodology.
This study was performed using in vitro wire myography. Although this
technique has achieved a wide degree of acceptability, concerns have
been expressed that the wires distort the shape of the blood vessel and
may damage the endothelium. In addition, there is no flow through the
lumen of the artery, and exogenously applied hormones, drugs, and
antagonists are administered to the adventitial surface of the vessel.
Consequently, investigators have begun to use pressure myography, which
necessitates the mounting of similarly sized segments of small arteries
on cannulas; this method maintains the physiological contour of the
vessel, does not traumatize the endothelial surface, and permits the
presentation of hormones and drugs to the luminal surface. Therefore,
there is the possibility that the methodology we used might have
influenced the outcome. With respect to morphology, we have shown that
pressure and wire myography provide largely similar results, and so we are confident that this is not a problem (12, 13). With regard to the
functional findings, relaxation of small arteries to acetylcholine is
similar with use of either method, whereas sensitivity to
norepinephrine is greater in pressurized vessels. However, there is no
evidence that methodology produces different changes in study
populations (12, 21). In summary, we are confident that the in vitro
methods employed have not influenced our findings.
Control subjects.
To make comparisons with our patient groups, we selected similarly aged
and gender-matched subjects with no history or evidence of
cardiovascular disease. These individuals had a significantly higher
average systolic blood pressure but diastolic pressures comparable to
our patient groups. Therefore, it is possible that we selected
previously undiagnosed hypertensive individuals into the control group.
In doing so we might have increased the arterial morphology parameters
and masked a change in heart failure patients. We believe this is
unlikely for the following reasons:
1) we would anticipate that further
readings of blood pressure over a protracted period would show a
decline in the individual values, and
2) the morphology readings we
obtained are very close to normotensive values that we have previously
published (9, 27). Therefore, we are confident that a morphological
abnormality in heart failure has not been missed.
Drug therapy for heart failure.
All our patients with heart failure were receiving a number of drugs in
addition to ramipril or placebo. It is possible that these agents might
have influenced our findings, but the distribution of such drugs was
comparable between the study groups, and we consider this unlikely.
Sample size and duration of follow-up.
It has to be conceded that the size of our study population is small.
Consequently, only mild and variable changes in arterial structure and
function might have been missed. This is entirely possible, although
Angus et al. (5) did find a functional change in their
smaller cohort of patients with severe heart failure, and our
morphological findings are in accord with our previously published data
on normotensive subjects (17, 27). Certainly, these in vitro studies
with their limited assessment of function may miss in vivo
abnormalities. Larger cohorts of patients would permit a more
comprehensive series of functional tests to be carried out. With regard
to the duration of follow-up, this varied widely (6-43 mo).
Although this was the same overall for both groups of patients with
congestive heart failure, the small numbers make it impossible to
examine whether structure and function change with time. A reinspection
of the fate of our patients after 3 yr has revealed just one death in
the placebo-treated group (17).
In conclusion, subcutaneous small arteries from placebo-treated
patients with clinical evidence of mild heart failure demonstrated no
significant differences in vascular morphology, constriction, or
relaxation compared with vessels from normal control subjects. Subcutaneous arteries were studied, since they are obtained from a
vascular bed that is readily accessible in patients and healthy control
subjects, although it is not clear how representative they are of the
peripheral vasculature as a whole. Treatment of patients with mild
heart failure with an ACE inhibitor significantly reduced diastolic
blood pressure and tended to increase arterial luminal diameter and
reduce media-to-lumen ratio. Our results have shown that ACE inhibitor
therapy was associated with an augmented constrictor response to
angiotensin II and norepinephrine in subcutaneous small arteries, which
may reflect upregulation of these receptor-mediated events as a result
of diminished levels of these hormones in vivo. The parallel change in
constrictor responses mediated by angiotensin II and -adrenergic
receptors after ACE inhibition supports the existence of a functional
interaction between these two systems in humans.
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FOOTNOTES |
Address for reprint requests: A. M. Heagerty, Dept. of Medicine,
Manchester Royal Infirmary, Oxford Rd., Manchester M13 9WL, UK.
Received 8 September 1997; accepted in final form 20 January 1998.
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Abstract
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