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From the National Heart and Lung Institute, Imperial College School of
Medicine, Hammersmith Hospital, London, UK.
Correspondence to J.S. Kooner, MD, FRCP, Consulting Cardiologist, National Heart and Lung Institute, Imperial College of Medicine, Hammersmith Hospital, Du Cane Road, London W12ONN UK.
Methods and Results—To test this hypothesis, we have determined
the effects of a standard liquid meal on whole heart and regional
myocardial blood flow, measured by means of dynamic positron emission
tomography (PET) with 15O-labeled water in 14 patients with
a reproducible history of postprandial angina and 7 matched control
subjects. The standard liquid meal precipitated angina pectoris in all
patients. Baseline whole heart blood flow was similar and increased
normally after the meal in patients (0.97±0.14 to 1.14±0.25 mL
· min-1 · g-1,
P<.04) as in control subjects (0.92±0.12 to 1.02±0.13
mL · min-1 · g-1,
P<.02). In contrast, the coefficient of variation of
blood flow increased significantly after the standard liquid meal in
patients (34±9%, P<.05 versus baseline) but not in
control subjects (17±7%, P=NS versus baseline). In
patients, analysis of regional myocardial blood flow
demonstrated decreased myocardial blood flow in territories supplied by
stenotic arteries (1.01±0.35 to 0.76±0.27 mL ·
min-1 · g-1, P<.03),
but there was an increase in blood flow in territories supplied by
normal arteries (0.89±0.16 to 1.34±0.25 mL ·
min-1 · g-1, P<.001)
after the meal.
Conclusions—The standard liquid meal induced angina
pectoris in patients with coronary artery disease. Although
whole heart blood flow increased appropriately for the greater cardiac
work, there was a redistribution of regional blood flow from
territories supplied by severely stenosed coronary arteries to
those supplied by less diseased or normal arteries. This redistribution
may be the cause of myocardial ischemia in postprandial angina.
Reduction in myocardial blood flow, caused by redistribution of blood
from the coronary to the splanchnic vascular bed or to
exercising muscles (in exertional postprandial angina), has been
proposed as a possible mechanism in postprandial
angina.1 However, studies in
animals3 and in healthy human
volunteers4 have not provided support for this
hypothesis. Others have suggested that an increase in cardiac work may
have an important role in postprandial
angina.2 5 6 Indeed, the heart rate does increase
after food both in normal subjects7 and in
patients with postprandial angina6 8 ; however,
the magnitude of this rise is not sufficient to cause a significant
increase in myocardial oxygen consumption.2 5 6
Evidence from previous studies suggests that stimuli increasing
sympathetic nervous activity, such as increased heart rate, mental
stress, and cold pressor, can reduce regional myocardial blood flow to
below resting levels.9 10 11 Similar changes may
occur in severely diseased vessels during sympathetic activation after
food. Redistribution of myocardial blood flow from regions supplied by
a severely stenosed coronary artery to those supplied by less
diseased, or normal vessels, might offer an explanation for
postprandial angina. To test this hypothesis, we have determined the
effects of a standard liquid meal on whole heart and regional
myocardial blood flow by using positron emission tomography (PET) with
15O-labeled water in patients with a reproducible
history of postprandial angina.
Study Protocol
Positron Emission Tomography
With the patient in the supine position, a 5-minute rectilinear
transmission scan was recorded with a ring source of
68Ge initially to facilitate the positioning of
the left ventricle within the window of view of the scanner.
Subsequently a 20-minute transmission was performed to correct all
emission scans for tissue attenuation. After the transmission scan,
radioactive gases were delivered at a constant rate by a standard
facemask used clinically for delivering oxygen (MC oxygen mask, Henlys
Medical). A blood pool scan was performed by inhalation of
15Olabeled carbon monoxide
(C15O), delivered at a rate of 500 mL/min, with 3
MBq/mL activity for 4 minutes. The inhaled C15O
rapidly forms [15O]carboxyhemoglobin. A
single-frame, 6-minute scan was started 1 minute after the end of
inhalation of the C15O. After a 10-minute period
(corresponding to approximately 5 half-life periods of
15O) to allow for decay,
15O-labeled carbon dioxide
(C15O2) was administered
for 3.5 minutes with 4 MBq/mL activity at a rate of 500 mL/min. The
C15O2 is immediately
converted to H215O by carbonic
anhydrase in the lung.12 A 25-frame scan was
recorded commencing 30 seconds before
C15O2 delivery and
continuing for a total of 7 minutes. A build-up scan over 3.5 minutes
and a washout scan over 3 minutes are thus produced (frame durations
were 1x30 seconds, 6x5 seconds, 6x10 seconds, 6x20 seconds, and
6x30 seconds).
PET Data Analysis
The reslicing of the images from the transaxial into the short-axis
views was performed as follows. For the definition of the reslice
parameters, the Heartool graphical user interface
(CTI/Siemens) was used. The optimal transaxial slice was selected,
generally that in which the left ventricular component of
the image was largest. A guiding line was drawn on the latter image
from the left ventricular apex, through the middle of the
chamber, to the base of the left ventricle. The left ventricle was
sliced parallel to this guiding line to produce oblique slices. The
optimal left ventricular oblique slice was then selected
(again, this was generally the oblique slice in which the left
ventricular component of the image was largest). A guide
line was drawn along the long axis, from the apex to the base of the
left ventricle, on this optimal oblique slice. The program was used to
define slices perpendicular to the long line of the oblique view. With
the reslice parameters thus defined, the act of reslicing
was carried out with an in-house reslicing program, which applies the
reslice parameters defined with Heartool, to the images
being resliced.
The blood volume image was produced from the C15O
data by dividing the raw image by the product of the average venous
blood radioactivity and blood density (1.06 g/mL). Regions of interest
were drawn within the left atrium on three consecutive image planes and
projected onto the dynamic
H215O images to generate
time-activity curves for these regions, the average being used as an
arterial input function. An extravascular volume image
(VEV) was constructed by subtraction of the blood volume image from the
normalized transmission image. The normalization was achieved by first
rescaling the transmission image such that the mean pixel count in a
region of interest situated in the left ventricle was 1.06 (the density
of blood). A conversion from milliliters to grams of tissue was then
made by dividing by the density of tissue (1.04 g/mL). After this, the
blood volume images were subtracted from the integrated time frames of
the washout phase of the H215O
scans. The VEV and extravascular
H215O images were used for the
delineation of four myocardial regions of interest corresponding to the
territories of distribution of the major coronary
arteries-septal, anterior, lateral, and inferoposterior-over five to
eight short-axis planes of the left ventricle. The regions of interest
were based on the outer section of 4x90 degree quadrants applied on
visual inspection by the investigators analyzing the PET data. (The
investigators analyzing the PET data were blinded with respect to the
subjects of the PET scans being patients or control subjects, as well
as with respect to the patients' angiographic data.) In patients with
stenosis of the left anterior descending artery, the anterior
and septal regions were designated as the stenosis-related
regions. In patients with stenosis of the right
coronary artery, the inferoposterior region was designated as
the stenosis-related region, and in those with stenosis
of the left circumflex artery, the lateral region was designated as the
stenosis-related region. Coronary stenoses were
scored as 0% to 30%, 30% to 50%, 50% to 70%, 70% to 90%, and
90% to 100%. Lesions <50% were classified as nonstenotic
and >90% as stenotic. The regions of interest were
superimposed onto the kinetic time frames recorded during the
C15O2 inhalation and
washout; this produced a plane-averaged time-activity curve for each
region, which, together with the arterial input function,
were fitted to a single tissue compartment tracer kinetic model to give
values for regional MBF (mL · min-1
· g-1) as previously
reported.14 In addition, whole heart MBF was
determined by defining additional regions of interest, each drawn to
encompass the whole of the left ventricle within each image plane.
These whole heart regions were superimposed onto the kinetic time
frames as described above for the subregions to provide a single whole
left ventricle time-activity curve before the calculation of MBF. Thus
whole heart and regional values of MBF were obtained. In addition, the
coefficient of variation of flow (COV) was also derived for MBF at rest
and after the liquid meal as an index of homogeneity of low
distribution. The COV was calculated per subject as the standard
deviation/mean of the whole heart MBF values, expressed as a
percentage.
Plasma Catecholamines
Statistical Analysis
Basal heart rate and blood pressure were similar in patients and
control subjects. Thirty minutes after the standard liquid meal, heart
rate increased but blood pressure was unchanged in patients and control
subjects. The heart ratexsystolic blood pressure product
(RPP), an indirect index of myocardial oxygen consumption, was not
significantly different at the onset of angina or during chest
discomfort 30 minutes after the meal compared with baseline
measurements in patients. The heart ratexsystolic blood
pressure product was increased 30 minutes after the meal compared
with basal levels in control subjects (Table 1
Positron Emission Tomography
Plasma Catecholamines
Postprandial angina has been attributed to reduced myocardial blood
flow because of redistribution of flow from the coronary
arteries to the splanchnic vascular bed8 or to
exercising muscles (in exertional postprandial
angina).1 However, our observations, based on
direct measurement of blood flow, using PET, indicate that whole heart
blood flow increases normally after the standard liquid meal in
patients with postprandial angina. An increase in cardiac work has also
been suggested as a possible mechanism in postprandial
angina.2 5 6 In this study the standard liquid
meal induced a significant increase in heart rate in postprandial
angina patients6 8 and in control
subjects.16 17 However, the magnitude of the rise
in heart rate was not sufficient to produce a significant change
in the rate-pressure product, a quantity known to increase
linearly with myocardial oxygen consumption in normal
subjects.18 It is well known that blood pressure
is an important determinant of myocardial blood flow, and it is
entirely consistent that whole heart blood flow after the
standard liquid meal is not significant if corrected for the prevailing
myocardial workload. However, it is not within the scope of
the current study to examine the relation between the relative regional
myocardial contributions to total cardiac work and regional myocardial
blood flow data. A possible role for regional myocardial work, in
influencing regional myocardial blood flow patterns, cannot be excluded
from results of this study.
There was an increase in plasma norepinephrine after the
meal in patients and control subjects (Table 2
Food ingestion is associated with the release of a variety of
gastrointestinal hormones19 21 as well as
norepinephrine. The relative importance of these
neurohormonal consequences in redistribution of myocardial blood flow
in postprandial angina is not known. Direct noninvasive measurements of
regional myocardial blood flow with PET after adrenoceptor
antagonists or octreotide may allow the role of
catecholamines and vasoactive gastrointestinal hormones to
be investigated more fully. An investigation of the effect of meals of
different food composition would also be of importance because previous
studies indicate that postprandial angina results predominantly
from the carbohydrate rather than fat or protein
component.22
In conclusion, direct noninvasive measurements of myocardial blood flow
after a standard liquid meal demonstrate that whole heart blood flow
increases to the same extent in postprandial angina patients as in
control subjects. In patients with postprandial angina, myocardial
ischemia presumably results from redistribution of blood from
regions supplied by stenotic coronary arteries to those
subtended by nonstenosed coronary arteries. On the basis of
these observations, postprandial angina might logically be prevented by
drugs that selectively reduce adrenergically mediated coronary
vasoconstriction in severely diseased coronary segments and
those that oppose metabolic vasodilatation in territories
supplied by less diseased or normal arteries.
Received February 6, 1997;
revision received December 1, 1997;
accepted December 1, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Regional Myocardial Blood Flow Redistribution as a Cause of Postprandial Angina Pectoris
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Postprandial angina
pectoris has been recognized for more than two centuries and can be
identified in up to 10% of patients with chronic ischemic
heart disease. Redistribution of myocardial blood flow, from a region
supplied by a severely stenotic coronary artery to
those supplied by less diseased or normal vessels, is a potential
mechanism of postprandial angina.
Key Words: angina • food • coronary disease • blood flow
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Postprandial angina
pectoris has been recognized for more than two centuries and can be
identified in up to 10% of patients with chronic ischemic
heart disease.1 It is even more common in
patients with severe coronary artery disease and unstable
angina.1 2 The
pathophysiological basis of postprandial angina is
not fully understood.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Study Population
We studied 14 consecutive patients, 12 men and 2 women 62±6
years old (mean±SD), with a clear and reproducible history of
postprandial angina defined as typical chest pain in the resting state
up to 1 hour after a standard liquid meal. All patients had
angiographically proven coronary artery disease (at least one
epicardial arterial stenosis of >70% luminal
diameter and a dominant right coronary artery), and 8 patients
had a previous history of myocardial infarction. All had stable
symptoms. The treadmill exercise ECG test was positive for
ischemia (>0.1 mV rectilinear or downsloping ST-segment
depression 80 ms after the J point) in all patients. Seven normal
healthy male subjects 55±11 years old (P=NS versus
patients), selected from hospital staff, were studied as control
subjects. None had cardiovascular symptoms or were
receiving any medication. All had normal resting ECG, a normal exercise
ECG at high workload, and normal thallium-201 myocardial perfusion scan
at rest and during exercise.
Antianginal medication (except sublingual nitrates) was
discontinued 14 days, and oral nitrates 24 hours, before the study day.
All subjects abstained from caffeine-containing drinks for 24 hours
before the PET study. The PET studies were performed after an overnight
fast, between 8 and 9 AM, with subjects in the supine
position. A standard liquid meal was administered over 10 minutes by a
drinking straw with subjects in the supine position. The meal comprised
500 mL of fresh full cream milk (energy value, 64 kcal per 100 mL;
total, 352 kcal, composed of 18.15 g protein, 25.85 g carbohydrate, and
19.25 g fat), plus 261.5 g of Complan (Heinz Ltd), a vitamin- and
mineral-fortified drink mix, with dried skimmed milk and vegetable oil.
The 261.5 of Complan consisted of 40.27 g protein, 159.78 g
carbohydrate, and 38.70 g of fat. The total energy value of the 261.5 g
of Complan was 1148, giving a total value of the liquid meal of 1500
kcal. In all patients and control subjects, simultaneous
heart rate, blood pressure (Dinamap, Critikon Inc), and whole heart and
regional myocardial blood flow measurements were made before and
exactly 30 minutes after a standard liquid meal. The patients were
monitored for symptoms and the time to onset of angina. A 12-lead ECG
(Mac 6, Marquette Electronics) was recorded (1) under baseline
conditions; (2) immediately after consuming the meal; (3) at the onset
of angina; and (4) after the angina had resolved. The project was
approved by the Research Ethics Committee, Hammersmith Hospital, and
the UK Administration of Radioactive Substances Advisory Committee
(ARAC). Written informed consent was obtained in each case. The study
conformed to Declaration of Helsinki principles.
PET scans were performed at the Medical Research Council
Cyclotron Unit, Hammersmith Hospital, with an ECAT 931 to 08/12
multislice positron scanner (CTI/Siemens). The scanner comprises eight
rings of bismuth germanate detectors, allowing 15 cross-sectional
images of the heart to be viewed simultaneously in a
10.5-cm axial field of view. Emission scans were reconstructed with a
Hanning filter with cut-off at the Nyquist frequency. The transaxial
resolution achieved was 8.4±0.7 mm, full width at half-maximum,
for the emission data at the center of the field of view.
The sinograms obtained were corrected for attenuation and
reconstructed on a MicroVAX II computer (Digital Equipment
Corporation), with dedicated array processors and standard
reconstruction algorithms. Images were transferred to a SUN 3/60
workstation for further analysis with Analyze (Mayo
Foundation)13 and Pro-Matlab (The Mathworks Inc)
software packages.
Blood samples for catecholamines were collected by
an indwelling venous cannula in the antecubital fossa, in
lithium-heparin tubes containing ethylene glycol-tetra acetic acid and
reduced glutathione. Samples were taken in the basal fasting state and
30 minutes after the meal. The tubes were placed immediately on ice.
Plasma was separated by refrigerated centrifugation and
stored at -70°C. Plasma norepinephrine and
epinephrine were determined by high-power liquid
chromatography.15 The assay is
sensitive to 20 pg/mL. The within-run coefficient of variation is
<7.5%. Interassay variability was 10% to 15%, and all samples were
assayed together.
All values are expressed as mean±SD. The two-tailed unpaired
Student's t test was used to compare the data on age, heart
rate, blood pressure, and rate-pressure product between the patient
and control groups. Differences in basal and postprandial whole heart
and regional myocardial blood flow responses were examined with one-way
ANOVA and Scheffé's test. Comparison within subjects between
resting and postprandial heart rates, blood pressures, and
rate-pressure products and myocardial blood flow were made with
Student's paired t test. A value of P<.05 was
considered statistically significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Clinical Observations
Twelve of the 14 patients developed characteristic anginal
symptoms within 22 to 30 minutes of the meal. Seven patients
additionally developed ischemic ECG changes. Control subjects
did not have symptoms or ECG changes. 
).
View this table:
[in a new window]
Table 1. Hemodynamic Responses to the
Standard Liquid Meal in Patients With Postprandial Angina and in
Control Subjects
Twelve of the 14 patients had chest discomfort during whole heart
and regional blood flow measurements 30 minutes after the meal.
Baseline whole heart blood flow was not significantly different and
increased to a similar extent after the standard liquid meal in
patients (0.97±0.14 to 1.14±0.25 mL ·
min-1 · g-1,
P<.04) and in control subjects (0.92±0.12 to 1.02±0.13
mL · min-1 ·
g-1, P<.02). After correcting for
the prevailing heart rate–blood pressure product, whole heart
blood flow did not show an increase after the standard liquid meal in
patients (1.64±0.44 to 1.77±0.76) or control subjects (1.12±0.24 to
1.17±0.30). The baseline coefficient of variation of blood flow (COV)
was similar in patients and control subjects (19±10% versus 13±5%,
P=NS). However, COV increased significantly after the meal
in patients (34±9%, P<.05, versus baseline) but not in
control subjects (17±7%, P=NS versus baseline, Fig 1). In the patient group, comparison of
myocardial blood flow was made between territories supplied by the
stenotic arteries and those supplied by nonstenotic
coronary arteries. Baseline myocardial blood flow was not
significantly different in regions subtended by stenotic and
the nonstenotic coronary arteries. After the meal,
myocardial blood flow fell in regions subtended by stenotic
arteries (1.01±0.35 to 0.76±0.27 mL ·
min-1 · g-1,
P<.03) but increased in regions subtended by
nonstenotic arteries (0.89±0.16 to 1.34±0.25 mL ·
min-1 · g-1,
P<.001, Fig 2). Calculated
coronary vascular resistance index increased in
stenotic (111±62 to 155±89 arbitrary units,
P<.001) but decreased in nonstenotic (119±38 to
80±29 arbitrary units, P<.001) arteries after the
meal.
View larger version (18K):
[in a new window]
Figure 1. Total myocardial blood flow in the basal state and
after the standard liquid meal in patients with postprandial angina
(n=14) and in control subjects (n=7).
View larger version (23K):
[in a new window]
Figure 2. Regional myocardial blood flow in territories
supplied by stenotic and normal arteries, in the fasting state,
and after the standard liquid meal in patients with postprandial
angina.
Plasma norepinephrine increased after the meal in
patients (3.9±0.3 to 5.1±0.4 pmol/mL, P<.002) and control
subjects (3.3±0.3 to 4.8±0.3 pmol/mL P<.002). Plasma
epinephrine did not change after the meal in patients
(0.67±0.1 to 0.79±0.2 pmol/mL) or in control subjects (0.63±0.2 to
0.78±0.2 pmol/mL).
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The principal findings of this study are that postprandial angina
is associated with: (a) a normal increase in whole heart myocardial
blood flow and (b) significant redistribution of regional myocardial
blood flow, from territories supplied by severely stenosed arteries to
those supplied by less diseased or normal coronary
arteries. ). This is likely to have resulted from
sympathetic activation and is absent after the meal in patients with
primary autonomic failure.19 In normal subjects,
the net effect of stimuli increasing sympathetic nervous activity is
coronary vasodilatation with an increase in myocardial blood
flow.9 10 11 In patients with coronary
artery disease, the coronary vasodilator reserve is exhausted
in territories supplied by arteries with stenoses >80% of the
luminal diameter.20 In such severely diseased
vessels, stimuli increasing sympathetic nervous activity, such as
increased heart rate, mental stress, and cold-pressor, can reduce
regional myocardial blood flow to below resting
levels,9 10 11 and the sympathetic activation due
to food ingestion may have the same effect. Consistent with
this, we found that in our patients, the standard liquid meal increased
calculated coronary vascular resistance in regions supplied by
stenotic arteries but reduced vascular resistance in regions
supplied by nonstenotic vessels. It may be hypothesized that in
patients with severe coronary artery disease, adrenergically
mediated coronary vasoconstriction cannot be overcome either by
vasodilatation caused by the local action of the products of
metabolism or by local endothelium-derived
relaxing factor nitric oxide10 11 ; release of the
latter is known to be impaired in atherosclerotic segments.
Vasodilatation of the coronary microcirculation in territories
supplied by normal or less severely diseased arteries may consequently
lead to diversion of blood from those territories supplied by more
severely diseased arteries (Table 3).
View this table:
[in a new window]
Table 2. Whole Heart and Regional Myocardial Blood Flow
Responses (in mL · min-1 · g-1) to the
Standard Liquid Meal in Patients With Postprandial Angina and in
Control Subjects
View this table:
[in a new window]
Table 3. Coronary Anatomy, Symptoms, and ECG
Changes After the Standard Liquid Meal in Patients With Postprandial
Angina
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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