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374
JACC Vol. 31, No. 2
February 1998:374 – 82
Heterogeneous Vasomotor Responses of Coronary Conduit and
Resistance Vessels in Hypertension
JAN L. HOUGHTON, MD, FACC, CATHY A. DAVISON, PHD, PATRICIA A. KUHNER, RN,
MIKHAIL T. TOROSSOV, MD, DAVID S. STROGATZ, PHD,* ALBERT A. CARR, MD†
Albany, New York and Augusta, Georgia
Objectives. The purpose of our study was to investigate the
relation between conductance and resistance coronary vasomotor
responsiveness in hypertensive patients without atherosclerosis.
Background. Although similar in morphology, conduit and
resistance coronary vessels differ importantly in size, function and
local environment and appear to be differentially affected in
certain disease processes, such as atherosclerosis and hypertension. However, little is known about the effect of hypertension on
contiguous coronary conduit and resistance vessels in humans.
Methods. Changes in coronary blood flow (a measure of resistance vessel reactivity) and coronary artery diameter (a measure
of conduit vessel reactivity) were investigated in response to
graded infusion of the endothelium-dependent agonist acetylcholine (ACh) in 98 patients with normal coronary arteries.
Results. In 31 normotensive, euglycemic patients, conduit and
resistance coronary artery responses to intracoronary infusion of
ACh were significantly correlated (r 5 0.73, p 5 1 3 1026),
although eight patients (26%) had constriction of conduit but
dilation of resistance arteries at peak effect. In 28 hypertensive
patients without left ventricular hypertrophy (LVH), conduit and
resistance artery responses to ACh remained significantly correlated (r 5 0.5, p 5 0.006), although 12 patients (43%) had
discordant findings. Finally, in 39 hypertensive patients with
LVH, conduit and resistance artery responses to ACh displayed
the lowest correlation (r 5 0.38, p 5 0.02), with 22 patients (56%)
demonstrating conduit artery constriction and resistance artery
dilation.
Conclusions. Despite angiographically normal coronary arteries, heterogeneous vasomotor responses (dilation and constriction) were demonstrated in contiguous conduit and resistance
arteries in normotensive and hypertensive patients referred for
cardiac catheterization because of chest pain. In addition to more
severe endothelial dysfunction among conduit and resistance
arteries, a greater frequency of discordant conduit and resistance
artery responses and resistance vessel constriction was found with
increasing severity of hypertension. Our study suggests differing
mechanisms of endothelium responsiveness to ACh among conduit and resistance coronary arteries.
(J Am Coll Cardiol 1998;31:374 – 82)
©1998 by the American College of Cardiology
The coronary vasculature is lined by an endothelial cell
monolayer, which plays an important role in regulation of
coronary blood flow through release of vasoactive substances
and modulation of vasoconstrictor stimuli (1– 4). Although
anatomically similar in morphology, conduit and resistance
coronary vessels differ importantly in size, function and local
environment and appear to be differentially affected in some
disorders, such as atherosclerotic cardiovascular disease and
hypertension (5– 8). Impairment of endothelium-dependent
vasodilation has been demonstrated in both conduit and
resistance coronary vessels in hypertensive disease (9 –11).
Similarly, endothelial dysfunction has been demonstrated in
the forearm circulation among adults and children with risk
factors for coronary disease (12–15). However, only a few
studies have systematically evaluated the relation between
conduit and resistance vasomotor function in contiguous human coronary vessels (16,17). Studies in isolated conduit and
resistance vessels from hypertensive rats have revealed both
discordant and similar alterations in contractile sensitivity
(18 –20). The purpose of our study was to investigate the
relation between conductance and resistance coronary vasomotor responses to the endothelium-dependent agonist, acetylcholine (ACh), in hypertensive subjects with and without left
ventricular hypertrophy (LVH) and in a comparison group of
similar normotensive subjects.
From the Division of Cardiology, Department of Medicine and Department
of Pharmacology and Neurosciences, Albany Medical College and *State
University of New York at Albany, Albany, New York; and †Augusta Preventive
Cardiology, Augusta, Georgia. This study was supported by Grant HL50262 from
the National Heart, Lung, and Blood Institute, National Institutes of Health,
Bethesda, Maryland.
Manuscript received February 3, 1997; revised manuscript received October
3, 1997, accepted October 14, 1997.
Address for correspondence: Dr. Jan L. Houghton, Division of Cardiology,
A-44, 47 New Scotland Avenue, Albany Medical College, Albany, New York
12208. E-mail: [email protected].
©1998 by the American College of Cardiology
Published by Elsevier Science Inc.
Methods
Patients. Patients were prospectively recruited for the approved investigational study (Albany Medical College Institutional Review Board) after clinical referral for cardiac catheterization for evaluation of chest pain. Written, informed
consent was obtained documenting the patients’ understanding
of the investigational nature of the protocol. The current study
0735-1097/98/$19.00
PII S0735-1097(97)00505-6
JACC Vol. 31, No. 2
February 1998:374 – 82
Abbreviations and Acronyms
ACE 5 angiotensin-converting enzyme
ACh 5 acetylcholine
BSA 5 body surface area
LVH 5 left ventricular hypertrophy
is part of a larger study whose purpose is to examine the effects
of hypertension, LVH, hemodynamically insignificant atherosclerosis, gender and ethnicity on coronary artery and arteriolar relaxation. Thirty-one normotensive and 49 hypertensive
subjects from the present study were previously included in a
report that described the relation between ethnicity and coronary vasoreactivity (21). Enrolled patients had normal epicardial coronary arteries documented during coronary arteriography. Patients were excluded from the study because of
coronary artery disease, significant valvular heart disease or
other serious medical disorders. Patients fasted for a minimum
of 8 h before the study. Current smokers were instructed to
refrain from smoking for a minimum of 8 h.
Patients were grouped by the presence of hypertension and
left ventricular mass hypertrophy. Hypertension was defined as
reproducible blood pressure measurements $140/90 mm Hg
or self-reported taking of antihypertensive medication. Left
ventricular hypertrophy was defined as left ventricular mass
(calculated from M-mode echocardiographic measurements)
indexed by body surface area (BSA) in excess of genderspecific normal values established by the Framingham Heart
Study ($131 g/m2 for men and $100 g/m2 for women) (22).
Diabetes mellitus was diagnosed by a self-reported history or
by a fasting serum glucose level .140 mg/dl. Twenty-eight
patients had hypertension without LVH and 39 had hypertension with LVH. A comparison group of 31 normotensive,
euglycemic subjects was studied using similar methodology.
Body mass index was calculated as weight in kilograms divided
by height in meters squared. Blood was obtained in the fasting
state for measurement of total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, lipoprotein a and glucose.
All patients were referred for cardiac catheterization for
evaluation of chest pain or an anginal equivalent. Chest pain
was classified as angina pectoris, atypical angina or noncardiac
chest pain. Angina pectoris was defined in the classic manner
as substernal chest discomfort (heaviness or pressure) brought
on by exertion and relieved by rest or nitroglycerin, or a
prolonged episode of anginal pain at rest requiring hospital
admission. Atypical angina was defined as chest pain with some
features of classic angina but with other characteristics not
generally associated with angina pectoris such as sharp or
pleuritic character or an intermittent relation to exercise.
Noncardiac chest pain had no features of angina pectoris other
than substernal location of chest pain. An anginal equivalent
was defined as symptoms or findings commonly associated with
ischemia in the absence of chest pain, such as dyspnea or heart
HOUGHTON ET AL.
HETEROGENEOUS VASOMOTOR RESPONSES
375
failure. Of normotensive patients, 19 (61%) were judged to
have angina pectoris, 9 (29%) atypical angina, 2 (7%) an
anginal equivalent and 1 (3%) noncardiac chest pain. Of 28
hypertensive patients without LVH, 12 (43%) had angina
pectoris, 14 (50%) atypical angina, 1 (3.5%) an anginal equivalent and 1 (3.5%) noncardiac chest pain. Finally, of 39
hypertensive patients with LVH, 20 (51%) had angina pectoris,
9 (23%) atypical angina; 8 (21%) an anginal equivalent and 2
(5%) noncardiac chest pain.
Of the 31 normotensive patients, 11 (35%) were taking
potentially vasoactive medications for treatment of chest pain.
These included 10 patients receiving drugs with coronary
vasodilating properties, such as nitroglycerin or a calcium
channel blocker, and one patient receiving both a calcium
channel blocker and a beta-blocker. In only one patient was a
vasoactive medication (nitroglycerin paste) used within 12 h of
cardiac catheterization.
Of the 28 hypertensive patients without LVH, 24 (86%)
were taking potentially vasoactive medications for treatment of
chest pain or hypertension. These included 10 patients receiving coronary vasodilator drugs alone, 4 patients receiving a
beta-blocker alone, 5 patients receiving both a vasodilator and
a beta-blocker and 5 patients receiving an angiotensinconverting enzyme (ACE) inhibitor or alpha-adrenergic blocking drug together with other drugs. In only two patients were
vasoactive medications used within 12 h of cardiac catheterization (beta-blocker in one patient and calcium channel
blocker in another).
Of the 39 hypertensive patients with LVH, 31 (79%) were
taking potentially vasoactive medications for treatment of
chest pain or hypertension. These included 13 patients receiving coronary vasodilating drugs alone, 2 receiving betablockers alone, 9 receiving both vasodilator and beta-blockers
and 7 receiving an ACE inhibitor or alpha-adrenergic blocker
together with other drugs. In nine of these patients, vasoactive
medications were used within 12 h of cardiac catheterization.
These included coronary vasodilator drugs in six patients,
calcium channel blockers and beta-blockers in two patients and
an ACE inhibitor in one patient.
Although only 12% of the study patients were taking
vasoactive medications within 12 h, 7 normotensive patients, 16
hypertensive patients without LVH and 25 hypertensive patients with LVH (49%) were taking long-acting calcium channel antagonists or ACE inhibitors within 24 h of the study. A
separate analysis revealed that there were no significant differences in peak responses to the endothelium-dependent and
-independent agonists among these patients when compared
with the larger group.
Left ventricular mass measurements. Left ventricular
mass was calculated using M-mode echocardiographic measurements made in accordance with the Penn convention and
corrected to agree with necropsy data as follows (23,24):
LV mass ~g! 5 1.04 ~@IVS 1 LVID 1 PWT#3 2 ~LVID!3! 2 13.7,
where IVS 5 interventricular septal thickness (cm); LV 5 left
ventricular; LVID 5 left ventricular internal dimension at
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end-diastole (cm); and PWT 5 left ventricular posterior wall
thickness (cm). Analyses were performed using the calculated
value of left ventricular mass indexed by BSA in meters
squared. Partition values for LVH were taken from the
Framingham Heart Study. Using BSA for indexing, normal
meant ,131 g/m2 for men and ,100 g/m2 for women (22).
Comparisons were made among normotensive subjects and
hypertensive patients with and without LVH using the partitioning system described.
Invasive coronary artery testing. After diagnostic cardiac
catheterization was performed, 7,000 U of intravenous heparin
was administered and a 0.018-in. (0.045-cm) Cardiometrics
Flo-Wire Doppler-tipped guide wire was advanced through a
7F or 8F coronary artery guiding catheter into the proximal to
mid portion of the left anterior descending coronary artery in
64 patients, the left circumflex artery in 29 patients and the
distal portion of the left main coronary artery in 5 patients. The
placement of this device was optimized according to Doppler
signal quality. At least 15 min elapsed between the end of the
diagnostic study and baseline coronary velocity measurements.
Coronary flow velocity signals were sampled at a preset fixed
distance of 5.2 mm from the device tip to minimize the effect
of turbulence caused by the presence of the measuring device.
After stable measurements of baseline coronary flow velocity
were obtained, drugs were infused in the left main coronary
artery to test the capacity for vascular relaxation by
endothelium-dependent and -independent mechanisms. Coronary flow velocity was continuously recorded on super VHS
tapes during drug infusions so that peak drug effect could be
identified during processing of data performed at a later date.
Coronary angiograms were obtained under baseline conditions
and at the end of each graded infusion of ACh.
Intracoronary drug infusion protocols. The following protocol was used to study endothelium-independent coronary
vascular relaxation. Incremental doses of adenosine were used
because of the potential for a dilutional effect of hypertension
and LVH in some patients, due to increased coronary blood
flow. Therefore, adenosine, 8 mg, was first administered by
bolus infusion through the guiding catheter into the left main
coronary artery. After return to the baseline values of coronary
flow velocity, blood pressure and heart rate, adenosine, 16 mg,
then 20 mg, was similarly administered. Typically, 60 s elapsed
between each bolus infusion of adenosine. The next protocol
was used to study graded responses during endotheliumdependent coronary vascular relaxation. An infusion monorail
catheter was advanced over the Doppler wire device and
placed near the tip, but still within the guiding catheter so that
ACh was infused into the left main coronary artery (assumed
blood flow 150 ml/min). After verification of stable velocity
tracings, 3 ml of ACh was infused over 2 min through the
infusion catheter at a rate of 0.15 mg/min (1028 mol/liter) using
a Medfusion (Harvard) syringe pump. A coronary angiogram
was obtained, and after return to the baseline values of
coronary flow velocity, blood pressure and heart rate, 3 ml of
ACh was infused over 2 min at a rate of 1.5 mg/min (1027
mol/liter); a third infusion was similarly administered at a rate
JACC Vol. 31, No. 2
February 1998:374 – 82
of 15 mg/min (1026 mol/liter). In the same manner, a final
infusion at a rate of 30 mg/min (2 3 1026 mol/liter) was
performed in 49% of the patients. Typically, 60 s elapsed
between the end of one infusion and the onset of the next.
Quantitative coronary angiography. Baseline angiography
of the coronary vessel undergoing study was performed in an
optimal right anterior oblique or anteroposterior projection so
that overlapping of branches and foreshortening of the region
of interest were minimized. Angiography was repeated in the
identical view after each infusion of ACh. Angiography was not
repeated after each bolus of adenosine, because it was assumed that epicardial coronary diameter changes were minimal in response to this drug (25). An optimal end-diastolic
cineangiographic frame was selected and coronary artery diameter measurements were performed at the site of Doppler
velocity measurements at baseline and after each infusion of
ACh. Measurements were performed using electronic digital
calipers (Sandhill Scientific). Area was calculated assuming a
circular cross-sectional profile. Percent change in coronary
vessel diameter above baseline was calculated in response to
each infusion of ACh. The contrast agent, iohexol, was used in
all studies. Digital caliper measurements were later performed
by a single investigator (J.L.H.) who had no knowledge of the
clinical and echocardiographic findings. Measurements were
repeated at least 1 year later in 27 patients randomly selected
from the study cohort. Linear regression analysis of intraobserver variability for measurement of coronary artery diameter
showed good reproducibility (r 5 0.92, SEE 5 0.26, p , 0.001).
Coronary artery blood flow measurements. Coronary artery blood flow was calculated as the product of mean coronary
blood flow velocity and coronary artery cross-sectional area at
the site of Doppler wire velocity measurements. Baseline
values were calculated before infusion of the predominantly
endothelium-independent agent, adenosine, and before infusion of the endothelium-dependent agent, ACh. Percent
change in coronary blood flow above baseline was calculated in
response to each infusion of adenosine and ACh.
Statistical analysis. Summary clinical data and outcomes
of the research studies (percent change in coronary blood flow
and in coronary diameter measurements in response to
endothelium-dependent and -independent agonists) are expressed as the mean value 6 SE. The unpaired Student t test
(for continuous variables) and the chi-square test or Fisher
exact test (for categoric variables) were used to assess statistical significance of group differences, where p , 0.05 was
considered significant. Using linear regression analysis, correlations between percent change in coronary blood flow after
ACh (a measure of resistance artery dilation) and percent
change in coronary artery diameter after ACh (a measure of
conduit artery dilation or constriction) were performed for 31
normotensive subjects, 28 hypertensive patients without LVH
and 39 hypertensive patients with LVH. Repeated measures
analysis of variance was used to test for differences found in
coronary blood flow and coronary artery diameter responses to
graded infusion of ACh, with the Bonferroni adjustment of
probability values for multiple comparisons.
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Table 1. Characteristics of 31 Normotensive Subjects, 28
Hypertensive Subjects Without Left Ventricular Hypertrophy and 39
Hypertensive Subjects With Left Ventricular Hypertrophy
Age (yr)
Female gender
Tobacco use
Diabetes mellitus
LVM/BSA (g/m2)
LDL (mg/dl)
BMI (kg/m2)
EF (%)
Normotensive
(n 5 31)
HTN Without LVH
(n 5 28)
HTN With LVH
(n 5 39)
46 6 2
13 (42%)
15 (48%)
0 (0%)
101 6 3
135 6 6
27 6 1
62 6 2
48 6 2
12 (43%)
10 (36%)
1 (4%)
98 6 3
132 6 7
32.5 6 1.7*
66 6 2
53 6 2*
27 (70%)*
19 (50%)
10 (26%)
149 6 5*
131 6 6
33 6 1*
64 6 2
*p , 0.05 for significant difference. Data presented are mean value 6 SE or
number (%) of patients. BMI 5 body mass index; BSA 5 body surface area;
EF 5 ejection fraction; HTN 5 hypertension; LDL 5 low density lipoprotein;
LVH 5 left ventricular hypertrophy; LVM 5 left ventricular mass.
Results
Patients. Ninety-eight subjects underwent invasive testing
of coronary artery and arteriolar relaxation. None of the
subjects had angiographic evidence of coronary artery disease.
Sixty-one patients (62%) were white and 37 (38%) were
African American. We have previously shown, in a cohort of
black and white patients referred for coronary arteriography
because of chest pain, that African American race is not
associated with excess intrinsic or acquired depression in
coronary vascular relaxation during peak effect of the
endothelium-dependent and -independent agonists, ACh and
adenosine, after adjustment for the presence of LVH (21).
Fifty-two subjects (53%) were women and 46 (47%) were men.
Thirty-one subjects were normotensive; 28 had hypertension
without LVH; and 39 had hypertension with LVH based on the
Framingham partitioning system described in the Methods
section. Other characteristics are shown in Table 1. This
reveals no significant differences in tobacco use, low density
lipoprotein cholesterol and left ventricular ejection fraction
among normotensive subjects, hypertensive patients without
LVH and hypertensive patients with LVH. Those with hyper-
Figure 1. Percent increase in coronary blood flow above
baseline in response to graded intracoronary infusion of the
endothelium-dependent agent ACh in 31 normotensive patients, 28 hypertensive patients without LVH and 39 hypertensive patients with LVH. Data are expressed as mean
value 6 SE. ACh1 5 acetylcholine infusion rate of 0.15
mg/min; ACh2 5 1.5 mg/min; ACh3 5 15 mg/min; AChP 5
peak response to ACh infusion rates of 15 or 30 mg/min.
377
trophy were slightly older, more likely to be women and more
likely to be obese when compared with normotensive subjects.
Endothelium-independent coronary microvascular relaxation. The response of the coronary microcirculation to the
endothelium-independent agent, adenosine, was evaluated in
31 normotensive subjects, 28 hypertensive patients without
LVH and 39 hypertensive patients with LVH. After adenosine,
percent increase in coronary blood flow above baseline was
similar among normotensive subjects and hypertensive patients
without LVH (234 6 10% vs. 232 6 16%), but markedly
depressed in patients with LVH (169 6 14%, p , 0.004).
Of the three incremental doses of adenosine, the peak
response occurred in the normotensive group after 8 mg in 7
(23%), after 16 mg in 15 (48%) and after 20 mg in 9 (29%). In
hypertensive patients without LVH, the peak response occurred after 8 mg in 7 (25%), after 16 mg in 10 (36%) and after
20 mg in 11 (39%). Finally, in hypertensive patients with LVH,
the peak response occurred after 8 mg in 5 (13%), after 16 mg
in 12 (31%) and after 20 mg in 22 (56%).
Endothelium-dependent coronary microvascular and epicardial relaxation. Figure 1 demonstrates the response of the
coronary microcirculation to the endothelium-dependent
agent, ACh. Similarly, Figure 2 demonstrates the response of
coronary epicardial vessels to ACh. After ACh, peak percent
increase in coronary blood flow was similar among normotensive subjects and hypertensive patients without LVH, although
slightly reduced in the latter group (213 6 22% vs. 184 6
28%). Similarly, responses of epicardial vessels (percent diameter increase above baseline) were not significantly different
among normotensive subjects and hypertensive patients without LVH, although the responses were qualitatively different
with dilation among normotensive subjects and mild constriction occurring among hypertensive patients (2.9 6 2.1% vs.
21.1 6 2.7%). However, significant depression in microcirculatory vasodilation (87 6 10%, p , 0.0005) and frank constriction of epicardial vessels (27.5 6 1.9%, p , 0.05) were found
in hypertensive patients with LVH.
Although the average response of conduit coronary arteries
in normotensive subjects was dilation in response to ACh,
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February 1998:374 – 82
Figure 2. Percent increase (negative numbers indicate constriction) in coronary artery diameter above baseline in response to graded intracoronary infusion of the endotheliumdependent agent ACh in 31 normotensive patients, 28
hypertensive patients without LVH and 39 hypertensive patients with LVH. Data are expressed as mean value 6 SE.
Abbreviations as in Figure 1.
there was a range of findings, from a 31% increase to a 22%
decrease in coronary diameter. Eight of 31 normotensive
subjects (26%) demonstrated vasoconstriction after ACh. In
hypertensive patients without LVH, the average response of
conduit coronary arteries to ACh was mild constriction, with a
range of findings from a 41% increase to a 29% decrease in
coronary diameter. Twelve of 28 such patients (43%) demonstrated vasoconstriction after ACh. Finally, in hypertensive
patients with LVH, the average response of conduit coronary
arteries to ACh was constriction, with findings ranging from a
9% increase to a 41% decrease in coronary diameter. Twentytwo of 39 such patients (56%) demonstrated vasoconstriction
after ACh.
In our study, the nearly universal response of coronary
resistance vessels to ACh at peak effect was dilation. Although
normotensive patients demonstrated an average increase in
coronary blood flow of .200%, the range was 15% to 500%.
Similarly, although hypertensive patients without LVH demonstrated an average increase in coronary blood flow of 184%,
the range was 37% to 737%. Finally, hypertensive patients with
LVH demonstrated an average increase in coronary blood flow
of 87%, with a range of 3% to 238%. Although there was
variation in the response of resistance vessels within each
grouping, normotensive subjects and hypertensive patients
without LVH both had markedly greater blood flow responses
than did hypertensive patients with LVH (excess increase [95%
confidence intervals]: 126% [73% to 179%] for normotensive
subjects and 97% [42% to 152%] for hypertensive patients
without hypertrophy).
Correlation between microcirculatory and conduit responses in normotensive subjects. Figure 3 shows the relation
between microcirculatory and conduit vessel responses at peak
effect of intracoronary infusion of ACh in 31 normotensive
subjects. A significant correlation was found between the two
variables (y 5 191 1 7.8x, r 5 0.73, p 5 1026). For the most
part, congruence was found among vasomotor responses of the
microvasculature and conduit vessels with absence of vasoconstriction in 23 (74%) of 31 subjects. In the 8 subjects with
conduit artery constriction, percent increase in microcirculation blood flow was significantly lower than in the 23 subjects
with no change or dilation of conduit vessels (99 6 28% vs.
253 6 24%, p 5 0.001). Other causes of endothelial dysfunction, such as increased age, hypercholesterolemia, male gender, tobacco usage and diabetes mellitus, were not disproportionately present among these eight subjects. Vasoconstriction
of the microcirculation occurred in only one normotensive
subject at $1026 mol/liter of ACh, but in three patients at
#1027 mol/liter of ACh. The single subject demonstrating
resistance vessel constriction during maximal and submaximal
ACh infusion also demonstrated diffuse conduit vessel constriction at high and low infusion rates. Resistance vessel
constriction occurring in two subjects during submaximal ACh
infusion was transient and not associated with conduit vessel
constriction.
Figure 3. Peak increase in coronary blood flow above baseline (percent) versus peak change in coronary artery diameter compared with
baseline (percent) after intracoronary infusion of ACh in 31 normotensive patients. A significant correlation was found between the two
variables (y 5 191 1 7.8x, r 5 0.73, p 5 1026).
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HETEROGENEOUS VASOMOTOR RESPONSES
379
Figure 4. Peak increase in coronary blood flow above baseline (percent) versus peak change in coronary artery diameter compared with
baseline (percent) after intracoronary infusion of ACh in 28 hypertensive patients without LVH. A significant correlation was found between the two variables (y 5 190 1 5x, r 5 0.5, p 5 0.006).
Figure 5. Peak increase in coronary blood flow above baseline (percent) versus peak change in coronary artery diameter compared with
baseline (percent) after intracoronary infusion of ACh in 39 hypertensive patients with LVH. A significant correlation was found between
the two variables (y 5 102 1 2x, r 5 0.38, p 5 0.02).
Correlation between microcirculatory and conduit responses in hypertensive patients without LVH. Figure 4 shows
the relation between microcirculatory and conduit vessel responses at peak effect of intracoronary infusion of ACh in 28
hypertensive patients without LVH. A significant correlation
was found between the two variables (y 5 190 1 5x, r 5 0.50,
p 5 0.006). However, after removal of the leverage point in the
upper right corner of Figure 4 (possible outlier), a significant
correlation no longer existed. This point plus two others in the
left mid quadrant differ from the overall pattern. The right
upper quadrant point (marked conduit and resistance vessel
dilation) represents the findings from a premenopausal, nonobese woman without diabetes or hypercholesterolemia who
had recently diagnosed hypertension. The two points in the left
mid quadrant (marked conduit constriction but normal resistance vessel dilation) represent the results of two middle-aged
obese men without diabetes but with hypertension of recent
onset and hypercholesterolemia. In the 12 patients with epicardial constriction, percent increase in microcirculation blood
flow was lower (although not significantly) than in the 16
subjects with no change or dilation of conduit vessels (146 6
29% vs. 212 6 42%, p 5 0.24). Other causes of endothelial
dysfunction were not disproportionately present among these
12 patients. Vasoconstriction of the microcirculation occurred
in no patient at $1026 mol/liter of ACh, but in seven patients
at #1027 mol/liter of ACh. Five of these seven patients also
demonstrated conduit vessel constriction.
Correlation between microcirculatory and conduit responses in hypertensive patients with LVH. Figure 5 shows
the relation between microcirculatory and conduit vessel responses at peak effect of intracoronary infusion of ACh in 39
hypertensive patients with LVH. A significant correlation was
found between the two variables (y 5 102 1 2x, r 5 0.38, p 5
0.02). In 22 patients with epicardial constriction, percent
increase in microcirculation blood flow was significantly lower
than that in the 17 subjects with no change or dilation of
conduit vessels (68 6 11% vs. 112 6 18%, p 5 0.04). Other
causes of endothelial dysfunction were not disproportionately
present among these 22 patients. Vasoconstriction of the
microcirculation occurred in only one patient at $1026 mol/
liter of ACh, but in 13 patients at #1027 mol/liter of ACh. The
single patient with resistance vessel constriction during maximal ACh infusion also demonstrated conduit vasoconstriction.
Ten of 13 patients with transient resistance vessel constriction
during submaximal ACh infusion demonstrated conduit vessel
constriction.
Discussion
The focus of our study was investigation of endothelial
function among contiguous conduit and resistance coronary
arteries in similar normotensive subjects and hypertensive
patients referred for cardiac catheterization because of chest
pain. Using the endothelium-dependent agonist, ACh, our
study shows that endothelium-mediated responses of conduit
and resistance coronary arteries are correlated most strongly
among normotensive subjects (r 5 0.73), less strongly among
hypertensive patients without LVH (r 5 0.5) and least strongly
among hypertensive patients with LVH (r 5 0.38). In response
to graded infusion of ACh, endothelium-dependent vasodilation of coronary resistance vessels was slightly depressed in
hypertensive patients without LVH and markedly depressed in
hypertensive patients with LVH when compared with normotensive subjects. Similarly, conduit vessels dilated in normotensive subjects after ACh, constricted slightly in hypertensive
patients without LVH and constricted significantly in hypertensive patients with LVH. Greater frequency of discordant
conduit and resistance artery responses and transient constric-
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tion of resistance arteries during submaximal infusion of ACh
were found with increasing severity of hypertension. As a point
of reference, vasomotor responsiveness of the microcirculation
to the endothelium-independent agonist, adenosine, was
nearly identical among normotensive subjects and hypertensive
patients without LVH. However, hypertensive patients with
LVH demonstrated significantly depressed vasomotor responses to adenosine. In our study, hypertensive patients with
and without LVH required a higher adenosine bolus than did
normotensive patients to elicit the greatest response.
Conduit vessel responses. In response to peak effect of
ACh, the average response of conduit coronary arteries was
dilation in normotensive subjects, mild constriction in hypertensive patients without LVH and significant constriction in
hypertensive patients with LVH. A range of findings from
dilation to constriction was present in all three groups, but was
shifted toward dilation in normotensive subjects and toward
constriction in hypertensive patients with LVH. As a group,
hypertensive patients with and without LVH demonstrated the
most heterogeneity of conduit artery responses. In all three
groups, conduit vessel constriction was, overall, associated with
resistance vessel dysfunction, although there were exceptions
found among hypertensive patients without LVH. Increasing
severity of hypertension was associated with an increasing
tendency for conduit artery constriction and associated resistance vessel dysfunction.
Resistance vessel responses. Although conduit vessels displayed a range of findings from dilation to constriction, the
usual response of resistance vessels to ACh was progressive
relaxation. Relaxation was greatest among normotensive subjects, followed closely by hypertensive patients without LVH,
but then trailed distantly by hypertensive patients with LVH.
Correlation between conduit and resistance artery responses. When present, depression in endothelial function
was usually, but not always, manifested in both conduit and
resistance vessels. Thus, epicardial coronary artery constriction
predicted depression in microcirculatory function in normotensive subjects and hypertensive patients without overt coronary atherosclerosis in our study. As a group, however, more
dispersion of responses was found among hypertensive patients without LVH, which may, in part, be related to varying
duration of disease and to the clinical heterogeneity of mild to
moderate hypertension. Although maximal ACh infusion
($1026 mol/liter) resulted in epicardial vasoconstriction in
43% of patients, microcirculatory vasoconstriction (as evidenced by decreased coronary blood flow when compared with
baseline) occurred in only two patients (2%) during maximal
infusion of ACh. Both of these subjects demonstrated conduit
artery constriction. However, transient vasoconstriction of the
microcirculation occurred in 23 patients in response to submaximal infusion of ACh (#1027 mol/liter), with conversion to
dilation in all 23 at greater infusion rates of ACh. Sixteen of
these 23 patients demonstrated conduit vessel constriction.
Explanations for a heterogeneous effect of ACh on
conduit and resistance vessels include the following possibilities: differing contractile sensitivity of conduit and resis-
JACC Vol. 31, No. 2
February 1998:374 – 82
tance vessel smooth muscle and differing release or efficacy
of endothelium-derived relaxing or constricting factors in
response to ACh. The latter possibility includes differences not
only in type but also in quantity of vasoactive substances
released by the endothelium. Some studies have suggested
that, unlike conduit arteries where nitric oxide is the principal
endothelium-derived relaxing factor released by the endothelium, resistance artery endothelium releases predominantly
endothelium-derived hyperpolarizing factor in response to
ACh (7,8,26,27). Because specific blockers of endotheliumderived relaxing factors were not administered during our
study, the exact mechanisms cannot be identified. Release of
both endothelium-derived relaxing and constricting factors
after exposure to ACh was previously demonstrated in aortic
rings from the spontaneously hypertensive rat, resulting in
depression of relaxation at higher concentrations of the muscarinic agonist (1026 to 1025 mol/liter) (28). Just as the
predominant type of relaxing factor released by the endothelium may differ between conduit and resistance coronary
vessels, so too may the predominant form of endotheliumderived constricting factor differ.
Although the vascular wall is morphologically similar
among coronary conduit and resistance vessels, certain differences exist. Like other vascular beds, the conduit vessels are
exposed to systemic arterial pressures, but a large pressure
drop occurs across smaller coronary arteries, leading to markedly lower perfusion pressures in the resistance arteries
(29,30). Unlike other vascular beds, the intramyocardial resistance coronary arteries are exposed to the throttling effect of
left ventricular contraction during each systole. Thus, coronary
perfusion is governed not only by the driving pressure and
resistance vessel tone, but also by the parenchymal resistance
encountered during each systole. Because of these special
characteristics, coronary blood flow occurs predominantly in
diastole in the left coronary artery (31). In hypertension, blood
pressure elevation usually precedes development of LVH.
Thus, the earliest adverse findings are expected in conduit
coronary vessels that are exposed to the ambient systemic
pressure. Later in the course of hypertension, development of
LVH contributes to increased parenchymal resistance and is
associated with resistance vessel endothelial dysfunction (10).
Our study suggests that coronary conduit vessels are affected,
on average, earlier and more prominently than resistance
vessels in the course of hypertensive disease. In addition, we
have shown that LVH appears to be a marker for resistance
coronary artery endothelial dysfunction.
Clinical implications. Endothelial dysfunction of the coronary arteries is found across a broad spectrum of conditions
in patients who are free of angiographic evidence of coronary
atherosclerosis (9,10,32–38). These conditions include increased age, systemic hypertension, LVH, cardiomyopathy,
hyperlipidemia, diabetes mellitus, chronic tobacco use and
estrogen deficiency. Not coincidentally, most of these conditions are risk factors for development of coronary artery
atherosclerosis (39). Endothelial function studies, performed
in the human forearm circulation, have contributed impor-
JACC Vol. 31, No. 2
February 1998:374 – 82
tantly to the understanding of endothelial dysfunction in
hypertension. These studies have demonstrated that peripheral
conduit and resistance artery responses to several endotheliumdependent vasodilator agonists (including ACh, bradykinin,
substance P and flow mediators) are significantly blunted in
hypertension (13–15). Several studies have also shown that
endothelial dysfunction begins early even before evidence of
atherosclerotic plaques and is present among asymptomatic
children and young adults at high risk for future development
of atherosclerosis because of unfavorable risk factor profiles
(12,14).
Our study concentrates on one risk factor, systemic hypertension, and the associated adverse effects on contiguous
conduit and resistance coronary artery endothelial function.
We found that conduit coronary vessels are affected earlier and
more prominently when compared with resistance arteries. In
hypertensive patients in our study, endothelial dysfunction was
generally manifested as frank constriction in conduit vessels
and as depressed dilation in resistance vessels. However, we
observed increasing frequency of coronary resistance artery
constriction with increased severity of hypertension during
submaximal (#1027 mol/liter) infusion of ACh. This constriction was subsequently reversed during maximal ($1026 mol/
liter) infusion of ACh in nearly all patients, suggesting that an
endothelium-derived relaxing factor ultimately overcame constriction. Other studies have reported the presence of resistance or conduit vessel constriction during submaximal infusions of ACh (9,10,27,40). The observations that hypertensive
conduit coronary vessels constrict in a progressive fashion and
resistance arteries demonstrate dilation or a biphasic response
after ACh suggest once again that the endothelium-derived
relaxing factor is qualitatively or quantitatively different among
conduit and resistance coronary arteries (17).
Hypertension may lead to coronary atherosclerosis, LVH
and cardiomyopathy. Development of atherosclerosis in conduit arteries is generally believed to be a consequence of
endothelial dysfunction in response to multiple known risk
factors (41). However, the etiology of cardiomyopathy secondary to hypertension is not fully understood. One contributory
factor may be diffuse resistance vessel endothelial dysfunction
resulting in depressed dilation or even transient constriction.
This could lead to intermittent vascular insufficiency, patchy
myocardial necrosis and ultimately cardiomyopathy.
Study limitations. A number of different technologies are
available for quantifying coronary diameter changes during
infusion of vasoactive drugs. Two techniques, automated edgedetection quantitative coronary angiography and cinevideodensitometry, allow accurate estimates of coronary diameter
and area in the absence of eccentric lesions (42– 45). Electronic
digital calipers are useful for performing serial angiographic
measurements because of simplicity and low cost. Although
this technique has been shown to consistently overestimate the
true diameter of phantoms, when serial measurements are
expressed as percent diameter change from baseline (as was
done in our study), comparable results were found using either
HOUGHTON ET AL.
HETEROGENEOUS VASOMOTOR RESPONSES
381
digital calipers or automated quantitative coronary angiography (42).
Because specific blockers of endothelium-derived relaxing
factors were not administered, we cannot definitively establish
that there were qualitative or quantitative differences in the
relaxing factor released by the endothelium of conduit and
resistance coronary arteries among our study patients. Administration of such blockers in nitric oxide– deficient blood vessels
would be expected to show little change in the ACh responses,
but significantly less dilator responses and greater vasoconstriction in those vessels with normal or near normal nitric
oxide production (46). Additional studies are required using
specific blockers of nitric oxide production such as NGmonomethyl-L-arginine or Nv-nitro-L-arginine. An alternative
but less sensitive approach would involve studying the response
of conduit and resistance vessels to infusion of L-arginine, the
precursor of nitric oxide in patients with demonstrable endothelial dysfunction.
Although our investigation focuses on vasomotor changes
in hypertension, there are multiple other conditions or factors
that may be involved in individual patients, including idiopathic depression in microvascular relaxation (syndrome X),
resistance to adenosine or ACh effect, variability in Doppler
velocity or epicardial diameter measurements and the other
classic risk factors for coronary atherosclerosis.
Our study design did not include the additional complexity
of simultaneous left ventricular diastolic pressure measurements, which would be necessary for accurate calculation of
microvascular diastolic resistance. Therefore, this study cannot
differentiate between the effects of tissue compression secondary to LVH and direct vasomotor changes, both of which could
contribute to impaired microvascular relaxation.
Although the patients in our study had normal coronary
arteriograms, their referral for cardiac catheterization because
of chest pain differentiates them from a purely volunteer group
with normal coronary arteries. Thus, our findings may not be
generalizable to normal subjects or those with causes of
endothelial dysfunction other than hypertension.
Conclusions. Despite angiographically normal coronary arteries, heterogeneous vasomotor responses (dilation and constriction) were demonstrated in contiguous conduit and resistance arteries in normotensive subjects and hypertensive
patients referred for cardiac catheterization because of chest
pain. In addition to more severe endothelial dysfunction
among conduit and resistance arteries, greater frequency of
discordant conduit and resistance artery responses and resistance vessel constriction were found with increasing severity of
hypertension. Our results suggest that the endotheliumderived relaxing factor elicited by ACh may differ in a qualitative or quantitative fashion among conduit and resistance
coronary arteries in hypertensive subjects referred for cardiac
catheterization because of chest pain.
We thank Dawn Burke for manuscript preparation and the staff of the cardiac
catheterization laboratory at Albany Medical Center for technical support.
382
HOUGHTON ET AL.
HETEROGENEOUS VASOMOTOR RESPONSES
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