Vol. 275, Issue 4, H1482-H1488, October 1998
Endothelial dysfunction in human intramyocardial small
arteries in atherosclerosis and hypercholesterolemia
Anne
Cooper and
Anthony M.
Heagerty
Department of Medicine, University Hospital of South
Manchester, Manchester M23 9LT, United Kingdom
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ABSTRACT |
Vascular
responses of human intramyocardial small arteries were examined in
vitro to assess the influence of atherosclerosis and risk factors for
coronary artery disease on endothelium-dependent relaxation. Recipient
hearts were obtained from patients with ischemic
(n = 14) and nonischemic
(n = 13) cardiomyopathy undergoing heart transplantation. Small intramyocardial coronary arteries (mean
internal diameter 313 ± 11 µm) were mounted on a wire myograph for measurement of morphology and isometric tension. Vasodilation was
examined after preconstriction with U-46619, a thromboxane A2 analog. Endothelium-dependent
relaxation to acetylcholine and bradykinin was impaired in patients
with ischemic compared with nonischemic cardiomyopathy
(P < 0.01 and
P < 0.001, respectively). Endothelium-independent relaxation to sodium nitroprusside was preserved. Incubation with
L-arginine (3 mmol/l) did not
improve endothelium-dependent relaxation to acetylcholine or
bradykinin. With the use of stepwise multivariate analysis,
hypercholesterolemia, but no other risk factor for atherosclerosis, was
independently associated with impaired endothelium-dependent relaxation
to acetylcholine (r = 
0.50,
P = 0.05) but not to bradykinin.
Endothelial dysfunction in intramyocardial small arteries may
predispose patients with nonobstructive epicardial atherosclerosis and
hypercholesterolemia to myocardial ischemia.
endothelium-derived relaxing factor; microcirculation
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INTRODUCTION |
THE VASCULAR ENDOTHELIUM plays a crucial role in
modulating vasomotor tone in both large conduit and small
resistance-sized arteries through the release of vasoactive hormones
such as endothelium-derived relaxing factor (EDRF), prostacyclin,
endothelium-derived hyperpolarizing factor (EDHF), and endothelin
(15).
It is well established that atherosclerosis often potentiates
vasoconstrictor responses and impairs endothelium-dependent relaxation
(10, 23). This has been demonstrated in human coronary epicardial
arteries by in vivo (14, 25) and in vitro (7) studies. However, the
coronary microcirculation is the major determinant of coronary blood
flow and myocardial perfusion (1). Animal studies in which a model of
atherosclerosis induced by a high-cholesterol diet was used suggest
that the functional consequences of atherosclerosis extend into the
coronary microcirculation despite the absence of overt atherosclerotic
lesions there (13, 21). Although the epicardial atherosclerosis induced
is similar to that in humans (13), the time for induction is much
shorter and levels of serum cholesterol are up to 20 times above
normal, levels rarely encountered in human coronary artery disease.
Because hypercholesterolemia is known to decrease endothelium-dependent
relaxation even before morphological evidence of atherosclerosis
appears (2, 23), abnormalities detected in the coronary
microcirculation could have been due to hypercholesterolemia rather
than proximal atherosclerosis per se.
Only a limited number of studies have examined the vasomotor control of
the human coronary microcirculation and have done so indirectly using
indexes of coronary blood flow through the whole coronary circulation
(6, 25). However, in vitro studies of intramyocardial small arteries
have certain advantages over in vivo techniques, because there is
considerable heterogeneity in responses of vessels of different size
and in vitro studies are not confounded by activation of compensatory
control mechanisms. The in vitro myograph permits the examination of
small arteries of ~300 µm. Intramyocardial small arteries of this
size contribute ~25% of total coronary resistance (1) and, unlike
epicardial arteries, do not develop atherosclerosis (3).
Our aims were to examine, in vitro, human intramyocardial small
arteries to determine 1) contractile
and dilator responses, 2) the
influence of proximal epicardial atherosclerosis and coronary risk
factors on endothelium-dependent and -independent relaxation, and
3) possible mechanisms for impaired
endothelium-dependent relaxation. In particular, we examined
endothelium-dependent relaxation to a number of receptor agonists
acting on different signal transduction pathways and the effect of
incubation with the EDRF precursor L-arginine.
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METHODS |
Patient demographics.
Human recipient hearts were examined from patients undergoing heart
transplantation for idiopathic and ischemic cardiomyopathy or
heart-lung transplantation for pulmonary hypertension secondary to
patent ductus arteriosus. All patients with idiopathic or ischemic cardiomyopathy had end-stage congestive heart failure. Diagnosis was
made preoperatively on the basis of coronary angiography demonstrating the absence or presence of coronary artery disease and/or
myocardial biopsy demonstrating evidence of cardiomyopathy and later
confirmed by histological examination of the explanted heart. An
assessment of left ventricular function was made by left
ventriculography and echocardiography.
Group A consisted of 13 patients with
normal nonatherosclerotic epicardial coronary arteries.
Group B consisted of 14 patients with
atherosclerotic epicardial coronary arteries and ischemic cardiomyopathy. Intramyocardial small arteries obtained from these patients were used to examine vasomotor responses and the influence of
proximal atherosclerosis and coronary risk factors on
endothelium-dependent and -independent relaxation. Coronary risk
factors identified included age, hypercholesterolemia, a family history
of coronary artery disease, smoking, hypertension, diabetes mellitus,
and male gender. Fasting cholesterol levels and blood pressure
measurements were recorded at the time of transplant assessment. No
patients were taking lipid-lowering therapy at the time of assessment
or heart transplantation. Hypertension was defined as a history of elevated blood pressure requiring antihypertensive therapy. A family
history was established if a sibling or parent had developed clinical
evidence of coronary artery disease below the age of 60 yr. Smoking was
defined as a previous history of cigarette smoking because no patients
were current smokers. Drug treatment before cardiac transplantation was
noted.
Group C consisted of 16 patients also
with ischemic cardiomyopathy. Intramyocardial small arteries from these
patients were used to examine the effects of
L-arginine on
endothelium-dependent relaxation to acetylcholine and bradykinin.
Myograph.
Human recipient hearts were obtained at the time of cardiac
transplantation and placed in cold physiological salt solution (PSS)
with the following composition (in mmol/l): 119 NaCl, 4.7 KCL, 2.5 CaCl2, 1.17 MgSO4, 25 NaHCO3, 1.18 KH2PO4,
0.026 K2-EDTA, and 5.5 D-glucose. Intramyocardial small
arteries were dissected from the left ventricle by following branches
of the left anterior descending artery and were cleaned of adherent fat
and myocardium. Vessel segments (2 mm) were mounted in a small vessel
myograph as ring preparations for measurement of morphology and
isometric tension (18). The vessels were incubated in PSS for 30 min
while heated to a constant temperature of 37°C and bubbled with
95% O2-5%
CO2.
The myograph was placed on the stage of a light microscope, and a
calibrated micrometer was used to determine morphology measurements by
water-immersion microscopy. The morphology measurements were converted
to "normalized" values (see below) with the assumption of a
constant media volume (19). The resting tension-internal circumference
relationship was obtained for each vessel by applying the Laplace law
(
P = 2T/l,
where P is transmural pressure, T is wall tension, and l is effective
diameter) (18). Vessels were then set to a normalized internal
circumference of
L0, at which the
active response is near maximal, where
L0 = 0.9L100 and
L100 is the
internal circumference that the vessel would have under a transmural
pressure of 100 mmHg. Lumen diameter was calculated at
L0 as
0.9L100/
.
Vessels were stimulated four times (2 min) with a 125 mM
potassium-saline solution (PSS with KCl substituted for NaCl) to determine vessel viability. Vessels that failed to develop an active
pressure of 10 kPa were discarded.
Pharmacological studies.
Vasomotor responses were assessed in intramyocardial small arteries
from groups A and
B. Cumulative logarithmic dose
responses were determined to the thromboxane
A2 analog U-46619
(10
9-105
mol/l), acetylcholine
(109-105
mol/l), and norepinephrine
(109-105
mol/l) in the presence or absence of propranolol
(106 mol/l). Vasodilation
was examined by preconstricting arteries with U-46619
(106 mol/l) to produce a
stable plateau before adding cumulative logarithmic doses of
vasodilator agents. Vasodilator responses were assessed to
acetylcholine
(109-105
mol/l), bradykinin
(1010-105
mol/l), substance P
(1011-106
mol/l), and norepinephrine
(109-105
mol/l) in the presence and absence of propranolol
(106 mol/l) and sodium
nitroprusside
(109-104
mol/l). Drugs were administered in a randomized order to minimize interference of any agonist on subsequent pharmacological responses, except for U-46619, which was examined first, and sodium nitroprusside, which was examined last.
The endothelium was removed by careful rubbing of the lumen wall with a
human hair in two arteries. Relaxation responses to acetylcholine,
bradykinin, and substance P in these arteries preconstricted with
U-46619 were assessed.
Endothelium-dependent relaxation to acetylcholine
(109-105
mol/l) and bradykinin
(1010-105
mol/l) was assessed in 12 patients with ischemic cardiomyopathy from
group C before and after
incubation with 3 mmol/l
L-arginine for 45 min to
determine whether impairment of endothelium-dependent relaxation
resulted from a deficiency of this physiological precursor of
EDRF. Time-control experiments were performed to ensure that there was
no deterioration in the response to these agents during this incubation
period (n = 4).
Statistical analysis.
Demographic and morphological data were compared using an unpaired
Student's t-test. Analysis of
variance for repeated measures was used to compare dose-response curves
in groups A and
B. Because there was a significant
difference in age and a near-significant difference in serum
cholesterol between groups A and
B, the effect of proximal
atherosclerosis and coronary risk factors on endothelium-dependent relaxation to acetylcholine and bradykinin were examined in these groups. Coronary risk factors were considered as continuous
and/or categorical variables. Simple linear regression analysis
was used to assess the effects of continuous variables (serum
cholesterol and age). The unpaired Student's
t-test was used to examine the effects
of categorical coronary risk factors [previous cigarette smoker,
family history of ischemic heart disease (IHD) and hypertension] and proximal atherosclerosis. Limited numbers precluded the evaluation of the effect of gender and diabetes on endothelial function. The
effects of various coronary risk factors and proximal atherosclerosis on endothelium-dependent relaxation to acetylcholine and bradykinin were then examined by multiple stepwise regression analysis. All data
are expressed as means ± SE. Significance was accepted at P < 0.05.
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RESULTS |
Demographic data.
Baseline demographic data for groups A
and B are shown in Table
1. The mean small artery internal diameter
was 316.7 ± 16 µm in group A and
312.8 ± 17 µm in group B. There
was a significant difference in the mean age
(P < 0.01) and a near-significant
difference in serum cholesterol (P = 0.06). Ten patients in each group were previous cigarette smokers, and
patients in group B included five patients with a previous history of hypertension and three patients with diabetes mellitus (2 diet controlled, 1 insulin dependent). There
was no difference in glucose levels at the time of surgery. Medication
usage at the time of transplantation in groups
A and B is indicated
in Table 2. Baseline demographic data for
group C are also shown in Table 1.
Morphology studies.
Morphological data for groups A and
B are shown in Table
3. There is no significant difference in
small artery internal diameter, intima thickness, media thickness,
media-to-lumen ratio, or cross-sectional area between the two groups.
Small artery studies.
U-46619, a thromboxane A2 analog,
produced a dose-dependent constriction. U-46619 was the only agonist
that produced significant vasoconstriction. There was no overall
difference between groups A and
B, and no significant difference in
the maximum tension induced (3.46 ± 0.46 mN in
group A, 2.74 ± 0.24 mN in
group B; Fig.
1).
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Fig. 1.
Logarithmic dose-response vasoconstriction (tension) to U-46619 in
groups A ( ) and
B ( ). Values represent means ± SE. Group A consisted of patients with
normal, nonatherosclerotic epicardial coronary arteries, and
group B consisted of patients with
atherosclerotic epicardial coronary arteries.
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No contractile response was obtained in vessels of either group to
norepinephrine in the absence or presence of propranolol. In
preconstricted arteries, norepinephrine produced a dose-dependent relaxation (maximum: 35.1 ± 8.9% in group
A, 22.1 ± 3.2% in group B; P = not
significant). Norepinephrine-induced relaxation was predominantly
-adrenergic because relaxation was attenuated but not abolished by
the presence of propranolol (maximum: 19.8 ± 8.6% in
group A, 10.5 ± 2.0% in
group B;
P < 0.05). There was no significant
difference in norepinephrine-induced relaxation between the two groups,
either in the absence or presence of propranolol.
In general, acetylcholine did not produce a contractile response,
although four vessels in group B
produced a minimal degree of nonsustained constriction (tension = 0.15 ± 0.04 mN/mm) at the highest concentration of acetylcholine,
105 mol/l. Acetylcholine
produced a dose-dependent relaxation in preconstricted arteries. Some
vessels reconstricted at the higher concentrations of acetylcholine.
Endothelium-dependent relaxation was significantly impaired in
group B compared with
group A in response to acetylcholine
(P < 0.01, Fig.
2).
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Fig. 2.
Percent endothelium-dependent relaxation to acetylcholine in
groups A () and
B (). Arteries were preconstricted
with U-46619. Values represent means ± SE.
ED50 values (logarithms of
concentration in mol/l) were 7.46 ± 0.08 (group
A) and 7.00 ± 0.13 (group
B). P < 0.01 between group A and
group B.
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In preconstricted arteries, bradykinin and substance P produced
dose-dependent relaxation. Endothelium-dependent relaxation to
bradykinin was significantly impaired in group
B compared with group
A (P < 0.001, Fig.
3). Although substance P produced
vasodilation, problems with tachyphylaxis were encountered. There was a
trend toward impaired endothelium-dependent relaxation to substance P
in group B, but this was not
significant (Fig. 4). In contrast, endothelium-independent relaxation to sodium nitroprusside produced identical relaxation responses in small coronary arteries from groups A and
B (P = 0.76; Fig. 5). Relaxation to
acetylcholine, bradykinin, and substance P was abolished by endothelial
denudation, suggesting that relaxation to these agonists is endothelium
dependent.
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Fig. 3.
Percent endothelium-dependent relaxation to bradykinin in
groups A () and
B (). Arteries were preconstricted
with U-46619. Values represent means ± SE.
ED50 values were 8.57 ± 0.18 (group A) and 7.50 ± 0.16 (group B). P < 0.001 between group A and
group B.
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Fig. 4.
Percent endothelium-dependent relaxation to substance P in
groups A () and
B (). Arteries were preconstricted
with U-46619. Values represent means ± SE.
ED50 values were 9.14 ± 0.19 (group A) and 8.80 ± 0.21 (group B).
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Fig. 5.
Percent endothelium-independent relaxation to sodium nitroprusside in
groups A () and
group B (). Arteries were
preconstricted with U-46619. Values represent means ± SE.
ED50 values were 6.65 ± 0.22 (group A) and 6.57 ± 0.27 (group B).
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Risk factors.
There were no significant relationships between relaxation responses to
bradykinin and age, cholesterol, hypertension, smoking, or family
history of IHD by univariate analysis. Proximal atherosclerosis significantly impaired relaxation to bradykinin at
107 mol/l
(P < 0.01),
108 mol/l
(P = 0.0001), and
109 mol/l
(P < 0.05) after adjustment for risk
factors by multiple linear regression analysis.
There were no significant relationships between relaxation responses to
acetylcholine and age, hypertension, smoking, or a family history of
IHD by univariate analysis. The maximum relaxation response to
acetylcholine (which was not necessarily at the highest concentration
of acetylcholine) and the relaxation response to acetylcholine at
105 mol/l both correlated
negatively with serum cholesterol (r = 0.50 and 0.46, respectively;
P < 0.05). Both proximal
atherosclerosis and serum cholesterol independently predicted the
acetylcholine response by multiple linear regression analysis.
Cholesterol had more influence at higher concentrations of
acetylcholine (105 mol/l
and maximum relaxation, P < 0.05),
whereas proximal atherosclerosis also influenced acetylcholine
relaxation at slightly lower concentrations [107 mol/l
(P < 0.01) and
106 mol/l
(P < 0.01)] and maximum
relaxation (P < 0.05).
Response to L-arginine.
Preincubation of small arteries from group
C with 3 mmol/l
L-arginine did not improve
endothelium-dependent relaxation to acetylcholine (Fig.
6) or bradykinin (Fig. 7).
Time-control experiments demonstrated that there was no decline in
responses to acetylcholine or bradykinin after the 45-min incubation
period (Fig. 8,
A and B, respectively).
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Fig. 6.
Percent endothelium-dependent relaxation to acetylcholine from patients
in group C with ischemic
cardiomyopathy before () and after () incubation with
L-arginine (3 mmol/l). Arteries
were preconstricted with U-46619. Values represent means ± SE.
Group C consisted of patients with
atherosclerotic epicardial coronary arteries.
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Fig. 7.
Percent endothelium-dependent relaxation to bradykinin from patients in
group C with ischemic cardiomyopathy
before () and after () incubation with
L-arginine (3 mmol/l). Arteries
were preconstricted with U-46619. Values represent means ± SE.
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Fig. 8.
Percent endothelium-dependent relaxation to acetylcholine
(A) and bradykinin
(B) from patients in
group C before () and after () a
45-min time-control period. Arteries were preconstricted with U-46619.
Values represent means ± SE.
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| |
DISCUSSION |
This is the first in vitro examination of human intramyocardial small
arteries. In contrast to its role in atherosclerotic epicardial
arteries, acetylcholine produces vasodilation rather than
vasoconstriction of intramyocardial small arteries. Both proximal
atherosclerosis and hypercholesterolemia are independently associated with an impairment of endothelium-dependent relaxation in
human intramyocardial small arteries. Endothelium-dependent relaxation
is impaired to more than one receptor agonist acting on different
signal transduction pathways in patients with epicardial atherosclerosis but is selectively impaired to acetylcholine in patients with hypercholesterolemia. A history of
hypertension, age, and previous smoking and a family history of IHD are
all coronary risk factors that were not associated with an impairment of endothelial function in intramyocardial small arteries.
Endothelium-independent relaxation is maintained, suggesting normal
vascular smooth muscle function. Furthermore, we demonstrated that
incubation with L-arginine, a
physiological precursor to EDRF, did not restore endothelium-dependent relaxation in patients with ischemic cardiomyopathy, unlike previous studies in hypercholesterolemia, suggesting adequate stores of L-arginine.
Proximal atherosclerosis is associated with impairment of
endothelium-dependent relaxation to both acetylcholine and bradykinin, which act on different intracellular signal transduction pathways, suggesting a nonspecific abnormality in endothelial function. This is
not accounted for by morphological abnormalities because human
intramyocardial small arteries of this size, in contrast to epicardial
arteries, do not develop atherosclerotic lesions (3). Morphological
data do not demonstrate any differences in media or intima thickness.
Impairment of endothelium-dependent relaxation has been demonstrated
previously (6) to acetylcholine in vivo in small arteries of patients
with proximal atherosclerosis. This observation can now be extended to
in vitro studies and to the bradykinin receptor. Although it is
uncertain whether endogenous acetylcholine plays a role in control of
vasomotor tone, bradykinin does play a role in humans in stimulating
the release of EDRF under baseline conditions and during increases in
flow (9). As shown by multivariate analysis, hypercholesterolemia is
associated with a selective impairment of endothelium-dependent
relaxation to acetylcholine, possibly due to disruption of the signal
transduction pathway. This selective impairment has been seen in human
epicardial arteries and animal models with progression to a generalized
impairment only when atherosclerosis has developed (22, 23). This
suggests that the mechanisms associated with impairment of
endothelium-dependent relaxation in intramyocardial small arteries in
the presence of proximal atherosclerosis and hypercholesterolemia are
different.
Other differences in the potential mechanism(s) responsible for
endothelial dysfunction are evident. EDRF ultimately causes relaxation
by activating guanylate cyclase in vascular smooth muscle.
Endothelium-independent relaxation to sodium nitroprusside was
maintained in ischemic cardiomyopathy, indicating that impaired endothelium-dependent relaxation is not secondary to an abnormal vascular smooth muscle response. Studies have suggested, however, that
hypercholesterolemia is associated with a mild impairment in
endothelium-independent relaxation in human small arteries from the
peripheral circulation (8).
L-Arginine undergoes
hydroxylation of its terminal guanidino nitrogen group to form EDRF, a
reaction catalyzed by nitric oxide synthase. Endogenous intracellular
stores of L-arginine are usually sufficient to saturate the enzyme nitric oxide synthase under normal
conditions. Incubation of intramyocardial small arteries from patients
with ischemic cardiomyopathy with
L-arginine did not improve
endothelium-dependent relaxation, suggesting adequate stores of
L-arginine. A lack of
improvement in this study could be attributed to the chosen
concentration of L-arginine or
incubation time, but identical parameters have been shown to improve
endothelium-dependent relaxation in our laboratory in
hypercholesterolemic human peripheral small arteries in the small
vessel myograph (8). Therefore, extracellularly added
L-arginine must penetrate
endothelial cells under these conditions. In contrast to its role in
atherosclerosis, L-arginine has
improved endothelium-dependent relaxation in hypercholesterolemia (5,
8, 13).
Because EDRF is degraded by oxygen-derived free radicals, impairment of
endothelium-dependent relaxation in atherosclerosis and
hypercholesterolemia could be due to an inadequate endothelial intracellular antioxidant defense system and accelerated degradation of
EDRF. A number of studies (16, 17) support the concept of accelerated
degradation rather than decreased production of EDRF in
atherosclerosis. Thus the mechanisms by which hypercholesterolemia and
atherosclerosis impair endothelium-dependent relaxation remain unknown,
although many potential mechanisms probably contribute.
A limitation to the study was the use of cardiomyopathy patients as
"control" patients and the presence of congestive cardiac failure
in both groups. However, it is clearly not possible to examine normal
human hearts in vitro. No unused donor hearts were available for study.
Cardiomyopathy has been shown to impair endothelium-dependent relaxation to acetylcholine in the coronary microcirculation, with a
modest impairment of endothelium-independent relaxation (11, 24). These
observations suggest endothelial dysfunction, but extravascular forces
may also have contributed to the impaired coronary blood flow response.
Endothelial dysfunction in idiopathic cardiomyopathy may be secondary
to heart failure. Recent studies (4, 12, 20) have demonstrated impaired
endothelium-dependent relaxation to acetylcholine in congestive cardiac
failure in peripheral and coronary arteries. Congestive cardiac failure
was present in patients from both groups, and therefore any impairment
in the acetylcholine response as a result of heart failure would not
necessarily be detected.
In conclusion, proximal atherosclerosis is associated with impairment
of endothelium-dependent relaxation via different intracellular signal
transduction pathways in human small intramyocardial arteries. It is
not secondary to an impaired responsiveness of vascular smooth muscle,
because endothelium-independent relaxation was normal, or to a
deficiency of L-arginine
substrate, because incubation with
L-arginine did not improve
endothelium-dependent relaxation. Hypercholesterolemia, but no other
risk factor, is associated with an impairment of endothelium-dependent
relaxation, but this abnormality is confined to the acetylcholine
response. Impairment of endothelium-dependent relaxation in
intramyocardial small arteries will be associated with a decrease in
coronary flow reserve and therefore will play an important role in the
pathogenesis of myocardial ischemia, exacerbating the
pathophysiological consequences of coronary artery disease.
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ACKNOWLEDGEMENTS |
We thank the cardiac transplantation team and coordinators at
Wythenshawe Hospital, Manchester, UK, for their help and cooperation in
providing specimens for this study.
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FOOTNOTES |
Address for reprint requests: A. Cooper, Dept. of Cardiology, Hope
Hospital, Scott Lane, Salford, Manchester M6 8HD, UK.
Received 20 October 1997; accepted in final form 22 June 1998.
| |
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Am J Physiol Heart Circ Physiol 275(4):H1482-H1488
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Abstract
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