PATHOPHYSIOLOGY AND NATURAL HISTORY
MYOCARDIAL BLOOD FLOW
Factors that modify the flow
intracoronary injections
response
to
HAKAN EMANUELSSON, M.D., STIG HOLMBERG, M.D., KJELL SELIN, M.D.,
AND
JAN WALLIN, M.D.
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
ABSTRACT Coronary sinus flow (CSF) was measured in seven patients with normal coronary
arteries (group A) during intracoronary injections of 6 ml arterial blood, 6 ml blood from the coronary
sinus, 3 and 6 ml isotonic saline, 3 and 6 ml hypertonic glucose, and 6 ml of a contrast agent (sodium
metrizoate). In 10 patients with coronary artery disease (group B), CSF was measured after administration of 6 ml isotonic saline, 6 ml sodium metrizoate, and 6 ml of another contrast medium (iohexol). In
group A, arterial blood did not affect CSF, while coronary sinus blood induced a 33% increase. After 6
ml isotonic saline, there was a 35% increase in flow and after hypertonic glucose an increase of 70%.
Metrizoate induced a rise in flow of 109%. In group B, the increase in CSF after intracoronary injection
of saline, metrizoate, and iohexol was 30%, 83%, and 67%, respectively. Blood from the coronary
sinus, in contrast to arterial blood, induced a marked rise in peak flow, suggesting a role for reactive
hyperemia secondary to myocardial hypoxia in this response. A similar mechanism might have been
operative after injection of isotonic saline, as well as after the hyperosmolar contrast agents. However,
additional mechanisms mediated by the high osmotic pressure of these substances, such as induction of
the Bezold-Jarisch reflex, which will induce coronary vasodilation, may have played a role. Finally,
when hyperosmolar agents are used, the possibility of some direct vasodilating properties of the agents
cannot be excluded.
Circulation 72, No. 2, 287-291, 1985.
AN INTRACORONARY INJECTION of a substance
will in most cases lead to a change in coronary blood
flow. Factors other than the pharmacologic properties
of the injectate can affect the flow response. Such
factors include the chemical composition and physical
properties of the compound, such as its hyperosmolality and oxygen content. When contrast media are injected in a coronary artery, there is a marked increase
in flow that is dependent on the hyperosmolality but
not on the iodine content of the agent.' The actual
mechanisms of the increase in flow are not well
known. The present study was conducted to try to
evaluate factors influencing the flow response to intracoronary injections. Various amounts of different substances were therefore injected into the left coronary
arteries of 17 patients during continuous measurement
of coronary sinus blood flow (CSF).
From the Division of Cardiology, Department of Medicine 1, and
Department of Radiology I, Sahlgrenska Hospital, S-413 45 Goteborg,
Sweden.
Address for correspondence: Dr. Hakan Emanuelsson, Division of
Cardiology, Department of Medicine l, Sahlgrenska Hospital, S-4 13 45
Goteborg, Sweden.
Received Nov. 26, 1984; revision accepted April 18, 1985.
Vol. 72, No. 2, August 1985
Material and methods
Patients. Seventeen patients who had been admitted to the
hospital for coronary angiographic examination due to anginalike chest pain were investigated. Seven patients (group A) had
angiographically normal coronary arteries. Two were women
and five men, and their median age was 57 years (range 39 to
62). Group B consisted of 10 patients, all of whom proved to
have significant coronary artery disease with narrowing of at
least one vessel of more than 70%. There were two female and
eight male patients in this group and their median age 57 years
(range 48 to 62). No cardiac medication was given for 12 hr
before the study. Informed consent was obtained from each
patient and the Hospital Ethics Committee approved the study.
Catheterization. A Judkins catheter was used to engage the
ostium of the left coronary artery of each patient. A thermodilution pacing catheter (Wilton-Webster Lab.) was positiond in the
coronary sinus. The position of the catheter was confirmed by
injection of radiopaque dye and was adjusted during flow measurement until there was a stable baseline flow curve. With a
bolus injection of 10 ml of isotonic saline in the right atrium
during temperature recording in the coronary sinus, the presence of reflux as a source of measurement error2 could be
detected and was eliminated when necessary by changing the
position of the catheter.
Measurements. The CSF was determined with the continuous-infusion thermodilution method.3 Isotonic saline solution at
room temperature was infused into the coronary sinus at a rate of
44 ml/min by infusion pump. Blood oxygen saturation was
determined by a photometric method4 and the erythrocyte volume fraction (EVF) was estimated after 10 min centrifugation of
287
EMANUELSSON et al.
1oo
(,
*
80-
*
cc
r
I
a)
60O
(1)
40O
a,
a)
20-
7==2,0t'1F
20
2s
/,17A
74
-
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
FIGURE 1. Changes in CSF after intracoronary injections in group A.
Values are mean + SEM *p < .007 compared with control value,
which is the p value necessary for statistical significance after adjustment for the multiplicity of testing (see text).
the blood sample. The electrocardiogram was continuously recorded with a bipolar chest lead with one electrode in the V9
position and the other in the right subclavicular region.
Procedure. Coronary sinus temperature and the electrocardiogram were recorded continuously before, during, and after
the intracoronary injections. All substances were administered
by injection by the same person throughout the study, and the
injection rate was 2 ml/sec. In group A, the following injections
were given: 6 ml arterial blood (drawn from the coronary artery
catheter), 6 ml coronary venous blood (obtained via the coronary sinus catheter), 3 and 6 ml isotonic saline, 3 and 6 ml
hypertonic glucose (30% solution, which corresponds to 1400
mOsm/kg), and 6 ml sodium metrizoate (Isopaque Coronar 370,
Nyegaard & Co A/S), which is an ionic contrast medium with
calcium added and with an osmolality of 2100 mOsm/kg.
There was an interval of at least 5 min between the injections.
Two injections of each substance were given and the mean
difference in the increase in flow between duplicate measurements was 8 + 3% and did not exceed 15% for any of the
agents. In the first three patients, repeat injections were also
given of solutions (saline and contrast medium) at body temperature. Since the flow response was within the limits of the
variation in the duplicate measurements mentioned above, only
solutions at room temperature were used in the remaining
patients.
ln group B, all injections were given during atrial pacing to a
rate 20% above resting heart rate. Three different substances
were injected: 6 ml isotonic saline, 6 ml sodium metrizoate, and
6 ml iohexol (Omnipaque 350, Nyegaard & Co). The latter is a
new nonionic and low osmolar (700 mOsm/kg) contrast agent.
At least 5 min were allowed between the injections. Two injections of each substance were given. The coronary flow was
measured during the first injection, and blood samples for analysis of oxygen saturation and EVF were collected at 0, 30, 120,
and 300 sec after the second injection. Atrial pacing was performed throughout the procedure in group B patients.
Calculations. CSF was calculated with the formula Fb = Fi
x k (Tb -Ti)/(Tb -Tm) I, where Fb = blood flow in the
-
288
coronary sinus (mlJmin); Fi = infusion rate of saline (ml/min);
Tb, Ti, Tm = temperature of blood, injectate, and mixture of
blood and injectate, respectively; k = a constant derived from
the density and specific heat of saline solution and blood.
Statistical methods. In group A, the effects on CSF of seven
substances were investigated, and a double-sided test was performed for each substance. To adjust for testing multiplicity,
Bonferroni's method was used.5 According to this technique,
the alpha error of an individual test is reduced to 0.05/7, which
approximates 0.007. This value corresponds to the probability
of one or more of the seven individual hypotheses being erroneously rejected. Thus, only a p value below .007 was considered
to indicate statistical significance. In group B, multiple comparisons of results with each substance at different time intervals
after intracoronary injections were performed (Wilcoxon
matched-pairs signed-ranks test). In accordance with the discussion above, Bonferroni's method was used, and thus only p
values less than .0167 (0.05/3) were considered to indicate
statistical significance. In addition, the reactions to the individual substances were tested against each other at the different
time intervals, and the p value was similarly corrected.
Results
Group A. All patients were in sinus rhythm before
and during the intracoronary injections and the mean
heart rate was not significantly changed after any of the
injections. Figure 1 illustrates the reaction of CSF to
injection of the various substances. This parameter
was not affected by the injection of arterial blood.
Blood from the coronary sinus, on the other hand, did
produce a 33 ± 12% increase after intracoronary injection. After 3 and 6 ml isotonic saline, the CSF rose
t6cc ARTERIAL BLOOD
0%
6cc COR. SINUS BLOOD
25%
13cc SALINE
24%
6cc SAUNE
29%
13cc 300% GLUJCO
53%
6cc 30% GLUCC5
4 4%/
16cc METRIZOATE
120%
FIGURE 2. CSF recordings in one patient in group A.
CIRCULATION
PATHOPHYSIOLOGY AND NATURAL HISTORY-MYOCARDIAL
D-O
0
O-
---
0
A
.
--
BLOOD FLOW
SALINE
IOHEXOL
{
A METRIZOATE
2.6 0o
0
0
._
2.2-
0
cJ
1.8
1.4
0
lOsec
5min
2 min
30sec
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
FIGURE 3. CSF in group B after intracoronary injections of isotonic saline, sodium metrizoate, and iohexol. Values are mean
+ SEM. Ap < .0167 compared with zero values. ap < .0167 for metrizoate values compared with iohexol and saline values. The
p value of .0 167 is the highest accepted for obtaining statistical significance after adjusting for testing multiplicity (see text).
zoate (83%). The corresponding values for iohexol and
saline were 67% and 30%, respectively. The same
pattern was noted regarding the oxygen saturation of
CSF and EVF, i.e., metrizoate produced the most
marked increase in oxygen saturation and the greatest
fall in EVF (figures 4 and 5).
22 + 9% and 35 + 11%, respectively. Hypertonic
glucose induced increments in flow that were two to
three times greater than those induced with isotonic
saline. The most pronounced increase in CSF was seen
after sodium metrizoate (109 + 38%). Figure 2 shows
typical responses of flow to various intracoronary substances in one patient.
Group B. Figure 3 illustrates the effects on CSF of
intracoronary saline, iohexol, and sodium metrizoate.
The peak increase was most pronounced after metri-
45.
Discussion
Injection of all but one of the various substances
tested into the left coronary artery elicited a transient
a
0
0
0
Co
:at
c
0-0 SALINE
0--
0 IOHEXOL
A.A
.
METRIZOATE
40
._n
(0)
0
0
0
35.
0
c
Cu
._
0
._
Co
c
30-
0)
x
0
25I
l
0
10sec
&a
30sec
ifi
FIGURE 4. Changes in oxygen saturation of coronary sinus blood in patients in group B. Values
significance are as in figure 3.
Vol. 72. No. 2, August 1985
5min
2 min
are mean +-
SEM. Symbols of
289
EMANUELSSON et al.
EVFsc
0.41 -
0.39-
0.37:.
0.35 -
A
.1a
0.33-
O-~J
SALINE
-----O
IOHEXOL
A.. ....fA METRIZOATE
.
A
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
0.31L
,
0
lOsec
,
30sec
I -
A
2 min
A
5 min
FIGURE 5. Changes in EVF in group B. Values are mean ± SEM. Symbols of significance are as in figure 3.
increase in CSF. The exception was arterial blood,
which did not induce any significant alteration in flow.
This implies that the injection per se was not a stimulus
for a change in coronary blood flow.
In group A patients, the increase in CSF varied
markedly depending on the substance injected. There
was a 20% to 30% rise in flow after injection of isotonic saline or coronary venous blood. Injection of
hypertonic glucose solution resulted in 60% increase
and after metrizoate the flow more than doubled. It
was also noted that the coronary flow response was
more marked when a larger volume of the same substance was injected.
The time sequence of the increase in blood flow
after injection of isotonic saline, iohexol, and metrizoate was demonstrated in more detail in the group B
patients. The maximal flow occurred at about 10 sec
after the injection and in these patients as well as in
those in group A, the most marked increase was seen
after metrizoate. At the time of increase in coronary
flow there was also a significant increase in oxygen
saturation of the coronary sinus blood. Again, the most
pronounced response was noted after metrizoate injection. The increase in oxygen saturation was short-lasting and returned to the baseline level at 20 sec after
saline and iohexol, while the reaction to metrizoate
lasted somewhat longer.
The observed changes in coronary hemodynamics
290
after intracoronary injections in this study resemble the
reactive hyperemia seen after a brief coronary artery
occlusion, when an increase in coronary sinus oxygen
saturation is regularly seen and there is an overpayment of flow as well as of oxygen debt.6
A similar flow response can be elicited by hypoxia.7 The mechanism of hypoxic vasodilation is
not known in detail. Local release of adenosine, increased extracellular potassium concentration, or local
prostaglandin synthesis are proposed but not proved
mechanisms for vasodilation.9I1 The most likely cause
is a direct action of lowered Po, on the coronary vasculature causing vasodilation. Experimentally, coronary
flow has been demonstrated to vary inversely with the
arterial oxygen content. Since the intracoronary injection of all substances except arterial blood produced
a short period of myocardial hypoxia in the present
study, this mechanism may be an important factor in
the reactive hyperemia observed in our patients.
There was a progressively increasing hyperemic response to the same amount of saline, hypertonic glucose, and metrizoate. This suggests gradually increasing hypoxic stress on the coronary circulation, which
might be explained by different degrees of hyperosmolality. The change in EVF, which was most marked
after metrizoate, suggests a varying degree of hemodilution for the different substances. If the hyperosmolar
solution causes diffusion of water from extravascular
CIRCULATION
PATHOPHYSIOLOGY AND NATURAL HISTORY-MYOCARDIAL BLOOD FLOW
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
to intravascular space, the volume of fluid with low
oxygen content passing the vascular bed will increase.
This will cause a more marked hypoxic stimulus of
reactive hyperemia. However, exact interpretation of
these changes cannot be made since dehydration of
erythrocytes in a hyperosmolar solution also could
contribute to changes in EVF.
Additional mechanisms might partly explain the
changes in coronary flow. For example, it has been
demonstrated that the intracoronary injection of contrast material induces bradycardia and peripheral vasodilatation (the so-called Bezold-Jarisch reflex).'2 1'
The explanation for this reaction is probably that mechanoreceptors in the coronary arteries are activated by
injection of hyperosmolar agents. Thus, coronary vasodilation due to this mechanism might contribute to
the increase in flow after injection of hypertonic glucose solution, iohexol, and metrizoate. On the other
hand, the increase in coronary flow caused by injection
of isotonic saline and coronary venous blood is not
explained by this type of reflex.
Direct vascular actions of the injected substances,
i.e., pharmacologic vasodilatation, could also have a
hyperemic effect. However, it seems improbable that
isotonic saline could have such an effect.
In conclusion, several factors seem to influence the
degree of reactive hyperemia after an intracoronary
injection. The hypoxic stimulus of the injection, direct
and/or indirect effects of hyperosmolarity, and phar-
Vol. 72, No. 2, August 1985
macologic properties of the substances injected seem
to be some of the most important determinants of the
response.
References
I .Grainger RG: Osmolality of intravascular radiological contrast media. Br J Radiol 53: 739-746, 1980
2. Mathey DG, Chatterjee K, Tyberg JV, Lekven J, Brundage B,
Parmley WW: Coronary sinus reflux. A source of error in the
measurement of thermodilution coronary sinus flow. Circulation
57: 778, 1978
3. Ganz W, Tamura K, Maracus HS, Donoso R, Yoshida S, Swan
HJC: Measurement of coronary sinus blood flow by continuous
thermodilution in man. Circulation 64: 181, 1971
4. Siggard-Andersen 0: Experiences with a new direct reading oxygen saturation photometer using ultrasound for hemolyzing the
blood. Scand J Clin Lab Invest 37: 45, 1977
5. Snedecor GW, Cochran WG: Statistical methods. Ames, Iowa,
1980, The Iowa State University Press, pp 115-117
6. Schwartz GG, McHale PA, Greenfield JC: Hyperemic response of
the coronary circulation to brief diastolic occlusion in the conscious
dog. Circ Res 50: 28, 1982
7. Gellai M, Norton JM, Detar R: Evidence for direct control of
coronary vascular tone by oxygen. Circ Res 32: 279, 1973
8. Gellai M, Detar R: Evidence in support of hypoxia but against high
potassium and hyperosmolarity as possible mediators of sustained
vasodilation in rabbit cardiac and skeletal muscle. Circ Res 35:
681, 1974
9. Katori M, Berne RM: Release of adenosine from anoxic hearts.
Relationship to coronary flow. Circ Res 19: 420, 1966
10. Rubio R, Beme RM: Regulation of coronary blood flow. Prog
Cardiovasc Dis 18: 105, 1975
11. Bache RJ, Dymek DJ: Local and regional regulation of coronary
vascular tone. Prog Cardiovasc Dis 24: 191, 1981
12. Zelis R, Caudill CC, Baggette K, Mason DT: Reflex vasodilation
induced by coronary angiography in human subjects. Circulation
53: 490, 1976
13. Perez-Gomez F, Garcia-Aguado A: Origin of ventricular reflexes
caused by coronary arteriography. Br Heart J 39: 967, 1977
291
Factors that modify the flow response to intracoronary injections.
H Emanuelsson, S Holmberg, K Selin and J Wallin
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
Circulation. 1985;72:287-291
doi: 10.1161/01.CIR.72.2.287
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1985 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://circ.ahajournals.org/content/72/2/287
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally
published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further
information about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/