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From the Cardiology Department, University Hospital, Zurich (J.F., P.K.,
T.S., R.H.) and Bern (O.M.H.), Switzerland.
Correspondence to O.M. Hess, MD, Cardiology, University Hospital, 3010 Bern, Switzerland.
Methods and Results—Coronary vasomotion of a normal
and a stenotic vessel segment was studied in 39 patients with
coronary artery disease during supine bicycle exercise before
and 9±3 months after PTCA. Luminal area changes were determined by
biplane quantitative coronary arteriography. There were 21
normotensive and 18 hypertensive patients who did not differ with
regard to clinical characteristics. Percent area stenosis
decreased after PTCA from 90% to 39% (P<0.001) in
normotensive and from 86% to 33% (P<0.001) in
hypertensive patients. Exercise-induced vasomotion of the normal vessel
segment was significantly different between normotensives and
hypertensives before (+19% versus +1%, P<0.01) and
after (+16% versus +3%, P<0.01) PTCA. In contrast,
stenotic vessel segments showed vasoconstriction in both
normotensive and hypertensive patients (
Conclusions—Normal coronary arteries show reduced
vasodilation during exercise in hypertensive patients that may be
explained by the presence of endothelial dysfunction.
Stenotic vessels demonstrate paradoxical vasoconstriction
during exercise in both normotensive and hypertensive patients. PTCA
reverses vasoconstriction by elimination of the flow-limiting
stenosis and prevention of coronary stenosis
narrowing during exercise in normotensive and hypertensive patients.
The response of the coronary arteries after PTCA is abnormal
after administration of various pharmacological agents and generally
results in coronary vasoconstriction in the animal
model14 15 and in humans.16
This indicates a depressed protective role of the
endothelium against vasoconstrictor influences. Thus,
the purpose of the present study was to evaluate the influence of
PTCA on coronary vasomotion in normotensive and hypertensive
patients. Specifically, we wanted to know whether dynamic exercise has
a different effect on coronary vasomotion of the dilated vessel
in patients with normal and in those with high blood pressure.
All patients were selected from a group of subjects undergoing bicycle
exercise and coronary arteriography on the basis of the
following inclusion criteria: (1) stable, exercise-induced angina
pectoris in patients with coronary artery disease; (2) written
informed consent to undergo the exercise study; (3) clearly visible
coronary arteries with a normal and a stenotic vessel
segment (2 different vessels) for quantitative evaluation; (4)
successful PTCA without restenosis at the follow-up examination
(residual area stenosis <75% or residual diameter
stenosis <50%); and (5) exercise coronary
arteriography before and after PTCA.
Exclusion Criteria
Definition of Arterial Hypertension
Definition of Coronary Risk Factors
Cardiac Catheterization
Study Protocol
Quantitative Coronary Arteriography
Statistical Analysis
Exercise and Hemodynamic Data
Heart rate and mean pulmonary artery pressure at rest and
during exercise were comparable in all groups (Table 3
Coronary Angiographic Data
Stenotic Coronary Arteries
Nonstenotic Vessel
Stenotic Vessel
First, an impaired production of nitric oxide may precipitate
coronary vasoconstriction during exercise. Because in
hypertension a diminished release of nitric oxide has been
reported,26 27 hypertensive patients may elicit
more pronounced vasoconstrictory effects that may have been at least
partially counterbalanced by the increase in perfusion pressure during
exercise.
Second, an increase in
Third, enhanced platelet aggregation with release of
thromboxane A2 and
serotonin may cause focal vasocontriction of diseased
epicardial arteries.29 In vivo,
serotonin induces paradoxical vasoconstriction in the
presence of coronary
atherosclerosis.30
Finally, a flow-induced (passive) collapse of the
atherosclerosis-free vessel wall within the
stenosis (Venturi mechanism) may induce coronary
vasoconstriction during exercise. It has been shown under in vitro and
in vivo conditions and in computer models that a flow-induced collapse
within tight stenoses can occur and may aggravate a preexisting
coronary lesion.1 31
Effect of PTCA
In the present study, coronary vasomotion of the dilated
segment was improved in normotensive and hypertensive patients; thus,
partial restoration of endothelial function, which
might be due to a quantitative increase in endothelial
surface after the coronary artery is enlarged by angioplasty,
can be assumed but is speculative because no direct measurements of
endothelial function have been performed. However, this
study did not reveal any vasoconstriction at the site of PTCA. This may
be due either to the more complex effects of the
physiological stimulus such as bicycle exercise on
coronary vasomotion or to the longer time period studied
between PTCA and follow-up than in other studies, which probably allows
more complete reendothelialization.
Conclusions
Received November 14, 1997;
revision received May 18, 1998;
accepted May 20, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Percutaneous Transluminal Coronary Angioplasty Reverses Vasoconstriction of Stenotic Coronary Arteries in Hypertensive Patients
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Endothelial
dysfunction of coronary arteries with impaired vasodilation has
been reported in patients with arterial hypertension.
However, the effect of dynamic exercise on coronary vasomotion
of a stenotic vessel segment before and after PTCA has
not yet been evaluated in these patients. 
exercise, -11% versus –
20%, P=NS), which was reversed after PTCA (+3% versus
+2%, P=NS).
Key Words: coronary disease • vasodilation • endothelium • hypertension • angioplasty
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Coronary vasomotion
plays an important role in the regulation of coronary blood
flow at rest and during physical exercise.1 2
Arterial hypertension is associated with morphological and
functional alterations of the endothelium that may
cause abnormal coronary vasomotion.3 4 5 6 7 8 9 10 11 12
Hypertensive patients, especially in the presence of coronary
atherosclerosis, show reduced vasodilator capacity
during exercise compared with normotensive
subjects.13
Methods
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Abstract
Introduction
Methods
Results
Discussion
References
Study Population
Thirty-nine men (mean age, 53±8 years) with coronary
artery disease were included in this prospective analysis.
Twenty-one patients (10 normotensives, 11 hypertensives) were studied
on a prospective basis, whereas 18 patients (11 normotensives, 7
hypertensives) were selected retrospectively. Twenty-one patients were
normotensive (mean age, 54±7 years) and 18 were hypertensive (mean
age, 52±9 years) before and 9±3 months after PTCA. The 21 patients,
who were studied on a prospective basis, were asked by written informed
consent to undergo repeated angiography 6 to 12 months after PTCA.
Patients were excluded when there was severe or unstable angina
pectoris, diffuse 3-vessel disease, inability to perform exercise
angiography, recent myocardial infarction (<1 month), large infarcts
with hypokinetic or akinetic regions, and renal or hepatic disease.
Hypertension was defined according to World Health Organization
criteria17 as a history of high blood pressure
(diastolic pressure 
95 mm Hg and/or
systolic values 160 mm Hg) requiring long-term therapy
and a sustained blood pressure elevation documented during
hospitalization in a drug-free period (drugs discontinued 24 hours
before cardiac catheterization). Patients were
considered to have normal blood pressure if continuous blood pressure
readings showed diastolic values <90 mm Hg and
systolic values <140 mm Hg. Patients with secondary
causes of hypertension and evidence of damage to end organs were
excluded.
Coronary risk factors such as
hypercholesterolemia, cigarette smoking, family
history (coronary artery disease in 1 patient's parents or
sibling <60 years), and obesity (body mass index 28
kg/m2) were evaluated in the present
analysis. There were no patients with diabetes mellitus. Serum
cholesterol was considered to be normal if it was 
200
mg/dL, according to the definition of the National
Cholesterol Education Program.18
Informed consent was obtained from all patients. Medication was
stopped 24 hours before cardiac catheterization.
Pressure measurements in the aorta and pulmonary artery were
performed in all patients, which has been described
previously.19 Diagnostic
coronary angiography was carried out according to the Judkins
technique. Quantitative coronary angiography was performed in
the right and left anterior oblique projections, but in some
patients, craniocaudal angulation was necessary for proper
visualization of the stenotic segment. Cinefilm was used as a
data carrier (filming rate, 50 frames per second). PTCA was carried out
according to current indications and techniques. Patients with large
dissections, stenting, insufficient results, or restenosis at
follow-up were excluded from the study. Area stenosis before
and after PTCA were calculated according to standard methods used in
our laboratory.
At the end of diagnostic
catheterization, biplane coronary arteriography
was carried out at rest with the patient's feet attached to the
bicycle ergometer (Siemens-Elema AG, model 380B). Exercise was begun at
50 to 75 W and was increased every 2 minutes in increments of 25 to 50
W. Coronary arteriography was carried out at the end of each
exercise level with the patient holding his or her breath during
injection of the contrast medium. Arteriograms at maximum exercise
level were used for analysis of coronary vasomotion.
The exercise test was terminated because of angina pectoris, fatigue,
or ST-segment depression >0.2 mV. At the end of the exercise test, 1.6
mg nitroglycerin was administered sublingually. Biplane
coronary arteriography was repeated 5 minutes thereafter. There
were no complications related to the study protocol. The whole
procedure was repeated 9±3 months after PTCA. All patients gave
written informed consent for the second evaluation.
Quantitative evaluation of biplane coronary arteriograms
was performed with a semiautomatic computer system, which has been
described previously.20 21 Interobserver and
intraobserver variabilities for this system are 4.1% and 2.1%,
respectively. Quantitative analysis was performed in a normal
vessel segment chosen from a nonstenosed artery unaffected by luminal
irregularities, and the stenotic vessel segment was taken from
a diseased artery with a localized stenosis of >50%
(quantitatively assessed). The stenosed vessel segments (culprit
lesion) were chosen only from the proximal two thirds of the respective
artery. Measurement sites were selected on the basis of the following
criteria: (1) sufficient filling of the vessel with
radiographic contrast medium, (2) high-quality
end- diastolic cineframe without motion artifacts,
(3) straightness of the vessel segment to be analyzed, and
(4) biplane x-ray views. Angiograms were measured with the investigator
blinded to the variables of interest and actual study sequence
(rest, exercise, or nitroglycerin). Luminal area
changes were determined during exercise (Ex, percent change compared
with rest=100%) and after administration of sublingual
nitroglycerin (Ntg, percent change compared with
rest=100%) before (baseline) and after successful PTCA.
Between-group comparisons with regard to clinical,
hemodynamic, and angiographic data were performed by
1-way ANOVA for continuous variables, followed by Scheffé's
procedure if the probability value was significant
(P<0.05). Fisher's exact test was used for categorical
variables, and a paired t test was used for data before
and after PTCA. All values in text and tables are expressed as mean±SD
and in figures as mean±SEM.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patient Characteristics
Baseline values were evenly distributed between normotensive and
hypertensive patients, as shown in Table 1
. Follow-up examination 9±3 months
after PTCA showed similar blood pressure (Table 3) and levels of
cholesterol values (normotensives, 231±66 mg/100 mL;
hypertensives, 245±41 mg/mL) compared with baseline. After successful
PTCA, functional NYHA classification improved significantly in
normotensives (2.0±0.6 before versus 1.4±0.5 after PTCA,
P<0.01) and hypertensives (1.8±0.5 before versus 1.4±0.6
after PTCA, P<0.01).
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Table 1. Patient Characteristics, Risk Factors, and Medical
Treatment Before Angiography in Normotensives and
Hypertensives1
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Table 3. Hemodynamic Data During Angiography Before and 9±3
Months After PTCA in Normotensives and
Hypertensives1
Exercise workload and percent workload (percent of the age-, sex-,
and height-corrected normal value) in patients in the upright and
supine positions before PTCA were higher in hypertensive compared with
normotensive patients, although this difference was statistically not
significant (Table 2). After PTCA,
exercise-induced ST-segment depression was significantly reduced in all
patients.
View this table:
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Table 2. Exercise Data Before (Upright Position) and During
(Supine Position) Catheterization Before and 9±3 Months After
PTCA1 
). Among normotensives and
hypertensives, left ventricular end-diastolic
volume index (75±17 versus 81±22 mL/m2,
P=NS), left ventricular ejection fraction (61±9
versus 65±6%, P=NS), and left ventricular mass
index (77±15 versus 84±15 g/m2,
P=NS) were similarly distributed.
Normal Coronary Arteries
The increase in coronary artery luminal area during
exercise (Ex, change in percent of control value) differed
significantly between normotensive and hypertensive patients before
(+19±15% versus +1±9%, P<0.01) (Figure 1) and after (+16±11% versus +3±9,
P<0.01) PTCA. Administration of 1.6 mg sublingual
nitroglycerin at the end of exercise was associated
with a significant increase in mean vessel area in normotensive and
hypertensive patients before (+26±19% versus 29±14%,
P=NS) and after (+23±12% versus 30±13%, P=NS)
(Figure 3) PTCA.
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Figure 1. Luminal area change during exercise ( Ex, %) of
normal coronary arteries before and after PTCA in normotensive
and hypertensive patients. Values are mean±SEM.
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Figure 3. Luminal area change ( CSA) during exercise (Ex)
in percent of resting cross-sectional area before and after PTCA and
after 1.6 mg sublingual nitroglycerin (Ntg) after PTCA
in normotensive and hypertensive patients. Reaction of the normal
vessel to exercise is abnormal in hypertensive patients.
Stenotic vessel shows an abnormal response (vasocontriction) to
exercise in normotensive and hypertensive patients before PTCA that is
reversed by PTCA. There is a vasodilatory effect of
nitroglycerin of the normal and stenotic vessel
in all patients. Values are mean±SEM.
Percent area stenosis decreased after PTCA from 90±25%
to 39±9% (P<0.001) in normotensives and from 86±9% to
33±15% (P<0.001) in hypertensives. The inner surface
(endothelium) of the stenotic vessel segment
increased after PTCA from 2.3±1.6 to 5.8±3.5 mm
(P<0.001) in normotensives and from 2.2±1.9 to
6.1±3.7 mm (P<0.001) in hypertensives. At baseline,
there was a nonsignificant difference in exercise-induced
vasoconstriction of the stenotic vessel segment between
normotensives (-11±24%) and hypertensives (-20±19%) (Figure 2). After administration of
nitroglycerin, vasodilation occurred in both groups
(+14±17% versus +15±20%, P=NS). After PTCA,
exercise-induced coronary vasoconstriction was abolished, and
exercise-induced vasodilation was similar in normotensives (+3±11%)
and hypertensives (+2±13%). Again, after administration of
nitroglycerin, there was vasodilation in normotensives
(19±9%) and hypertensives (+25±14%) (Figure 3).
View larger version (19K):
[in a new window]
Figure 2. Luminal area change during exercise ( Ex, %) of
stenotic vessel segments before and after PTCA in normotensive
and hypertensive patients. Values are mean±SEM.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The present study is the first to assess the effect of PTCA on
coronary vasomotion in hypertensive patients. There were 3
important findings. First, hypertensive patients with angiographically
documented coronary artery disease reveal a blunted
vasodilatory response of the normal vessels compared with normotensive
subjects. Second, hypertensive and normotensive patients show
exercise-induced vasoconstriction of stenotic vessel segments.
Third, successful PTCA reverses the constrictive response of the
stenotic coronary arteries to exercise in patients with
coronary artery disease.
Coronary vasodilation during exercise is dependent on an
intact endothelium with adequate production of
nitric oxide. Recent human data indicate that
endothelial dysfunction occurs very early in the
development of atherosclerosis, even before the
appearance of stenotic lesions, resulting in an abnormal
coronary vasomotor response to
acetylcholine.22 23 24 25 The present study
compared the vasomotor response to exercise of angiographically
"normal" vessels in patients with coronary artery disease.
In normotensive subjects, these normal vessel segments dilated during
exercise by 16%, whereas hypertensive patients did not show
coronary vasomotion. Hypertension has direct structural and
functional effects on the coronary vessel wall, leading to
endothelial dysfunction with vasoconstriction of
angiographically normal coronary arteries in response to
intracoronary acetylcholine.7 8 In the
present analysis, however, blunted coronary
vasodilation but not vasoconstriction of normal coronary
vessels was observed during exercise, which is probably due to the more
complex effects of a physiological stimulus such as
bicycle exercise on coronary vasomotion than that of
pharmacological compounds. A major difference between the 2 stimuli is
certainly that blood pressure (coronary driving pressure) rises
during exercise but falls with pharmacological vasodilation. The
endothelium-independent dilator capacity after
nitroglycerin was maintained in both hypertensive and
normotensive patients. This suggests a preserved function of the smooth
vasculature but makes likely a primary defect of the
endothelium-dependent regulation of the epicardial
coronary arteries in hypertensive patients with
coronary artery disease.
Exercise-induced vasoconstriction of the stenotic vessel
segments was observed in hypertensives that was, however, similar to
that in normotensives. The exact mechanism responsible for the decrease
in minimal luminal area of the stenotic artery during exercise
is not clear but might involve different interacting mechanisms: 
-adrenergic tone during exercise has been
associated with coronary artery vasoconstriction, whereas an
increase in ß-receptor tone is accompanied by coronary
vasodilation.28
In the acute phase after PTCA, the reaction of the
coronary arteries to this procedure is complex and generally
results in vasoconstriction of the dilated vessel
segments.32 33 Endovascular interventions such as
PTCA expand the artery lumen, resulting in an increased laminar shear
stress that tends to enhance endothelial cell migration
and thereby facilitate the reendothelialization and
improvement in endothelial
function.34 Histological
examinations of reendothelialization late after PTCA
have shown in the experimental animal that the
neoendothelium has functional properties similar to the
normal endothelium but that the cells of the
neoendothelium are smaller with a different shape and
alignment compared with normal cells.14 15 35 The
physiological response of the coronary
arteries to different pharmacological substances in a late phase after
the intervention results in vasoconstriction in the animal
model14 15 and in humans.16
This response indicates that in the chronic regenerated state, the
protective role of endothelial cells against
vasoconstriction is depressed, which may favor the reaction to
aggregating platelets,14 the activation of
serotonergic receptors,15 and/or less
production of endothelium-derived relaxing
factors. In 1 study, long-term administration of
L-arginine, the precursor of nitric oxide, enhanced
neoendothelium-dependent relaxation of injured rabbit
iliac arteries.36 Furthermore, the extent of
anatomical recovery of the endothelium after denudation
plays an important role in restoring coronary vasodilation
after PTCA. Hayashi et al35 demonstrated in the
animal model a direct correlation between the vessel area recovered by
neoendothelial cells at the denuded site and percent
recovery of reactive vasodilation.
In the present study, exercise-induced coronary
vasodilation is blunted in hypertensive patients with normal
coronary artery segments compared with normotensive subjects.
In agreement with previous findings, this observation is compatible
with the presence of endothelial dysfunction in
essential hypertension. However, the behavior of stenotic
vessels during exercise is not affected by the presence or absence of
arterial hypertension either before or after PTCA. This is
probably due to complex interrelated mechanisms such as impaired
production of nitric oxide, increased -adrenergic
stimulation, enhanced platelet aggregation, and flow-induced
collapse of the disease-free vessel wall within the stenosis
during high-flow situations such as physical exercise. Mechanical
reduction of the coronary stenosis by PTCA prevents
exercise-induced vasoconstriction of the stenotic vessel
segment in normotensive and hypertensive patients, probably because of
partial restoration of endothelial function and
attenuation of the vasoconstrictory effects. Thus, successful PTCA
improves myocardial function by 2 mechanisms: (1) elimination of the
flow-limiting stenosis and (2) prevention of coronary
vasoconstriction during exercise.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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