(Circulation. 1995;91:1624-1628.)
© 1995 American Heart Association, Inc.
Articles |
Loss of Flow-Dependent Coronary Artery Dilatation in Patients With Hypertension
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993.
From the Service d'Explorations Fonctionnelles et Institut National de la Santé et de la Recherche Médicale Unité 251, Centre Hospitalier et Universitaire Xavier Bichat, Paris, France.
Correspondence to Isabelle Antony, MD, Hôpital Louis Mourier, CHU Xavier-Bichat, INSERM U. 251, 178 rue des Renouillers, F-92700 Colombes, France.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Abnormal endothelium-dependent coronary response to acetylcholine has been shown in patients with essential hypertension. We tested the hypothesis that flow-dependent dilatation, which has been shown in normal human coronary arteries, is impaired in hypertensive patients.
Methods and Results The coronary vasomotor response to maximal increase of blood flow induced by papaverine was studied in 10 control subjects and in 14 hypertensive patients with no other risk factors and angiographically normal coronary arteries. After the injection of papaverine in the midportion of the left anterior descending coronary artery (LAD), the diameter of the proximal LAD (LAD1) was measured by quantitative angiography, whereas that of the proximal circumflex artery (LCx) served as control segment. Estimates of coronary blood flow in the distal LAD (LAD2) were calculated by intracoronary Doppler flow velocity measurements. An increase in LAD2 blood flow of 521±41% (P<.001) in control subjects was associated with a 17.0±3.3% dilatation of the LAD1 (P<.001) and with no significant change in the diameter of the LCx. In hypertensive patients, despite a comparable increase in LAD2 blood flow of 406±32% (P<.001), the LAD1 failed to dilate (-0.4±0.6%, NS). The dilative response to isosorbide dinitrate was similar in control subjects and hypertensive patients (30.0±4.1%, P<.001 and 21.9±1.9%, P<.001, respectively).
Conclusions Thus, the flow-mediated coronary dilatation is lost in hypertensive patients, and this may impair normal dilatation observed in response to an increase in myocardial metabolic demand.
Key Words: hypertension • arteries • blood flow • vasodilation
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Abnormal endothelium-dependent coronary vasomotor response to acetylcholine has been demonstrated in epicardial and resistance vessels of patients with hypertension and normal coronary arteries.1 2 The response to the increase in blood flow, which is another endothelium-mediated stimulus, has never been assessed in hypertensive patients. Flow-dependent dilatation has been shown in normal human coronary arteries3 4 and participates in a physiological way in the vascular tone control by changes in flow. In the present study, we evaluated the flow-dependent response in angiographically normal coronary arteries of patients with hypertension by injecting papaverine selectively into the midportion of the left anterior descending coronary artery (LAD) and measuring changes in the diameter of the proximal LAD secondary to increase in flow.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patient Selection
Fourteen patients with hypertension and 10 normotensive control subjects undergoing diagnostic coronary angiography for evaluation of chest pain were studied. Responses to the cold pressor test of 10 hypertensive patients and 9 control subjects have been reported in a previous study.5 Control subjects had a supine systolic blood pressure <140 mm Hg and a diastolic blood pressure <90 mm Hg. All hypertensive patients had a well-established history of elevated blood pressure >140/90 mm Hg, with at least four sets of readings taken at 1-week intervals. Hypertension was diagnosed recently in 9 patients who had never been treated and <1 year ago in the 5 others, in whom antihypertensive therapy was discontinued at least 3 weeks before cardiac catheterization. Patients who had a history of smoking more than five cigarettes a day or of diabetes mellitus and patients with total cholesterol serum level >5.70 mmol/L or LDL cholesterol >3.70 mmol/L were excluded. None of the patients had a family history of coronary artery disease. Left ventricular systolic function assessed by two-dimensional and M-mode echocardiography was normal in all control subjects and hypertensive patients. Left ventricular dimensions and septal and posterior wall thicknesses were measured at end diastole according to the American Society of Echocardiography guidelines.6 The left ventricular mass index was calculated at end diastole by the Penn convention.7 After the diagnostic coronary arteriography was performed, patients were included by consensus of two experienced investigators upon immediate review of the angiograms if coronary arteries were angiographically normal without luminal irregularities. The study protocol was approved by the institutional review committee of the University of Kremlin-Bicêtre. All patients gave written informed consent before cardiac catheterization.
Catheterization Protocol
Patients were studied in the fasting
state. Nitrate therapy,
when given, was withheld for at least 24 hours. No premedication was
administered; 1% lidocaine was used for local anesthesia, and 5000 U
IV heparin was administered. Coronary arteriography was performed by
the percutaneous femoral approach using 6F catheters. After
documentation of normal coronary arteries, at least 15 minutes were
allowed to elapse. After additional administration of 5000 U heparin,
an 8F guiding catheter was positioned in the left main coronary artery.
A 3F 20-MHz coronary Doppler catheter (Monorail Doppler 3, Schneider
Europe AG) connected to a single-channel 20-MHz pulsed Doppler
velocimeter (model MDV-20 Single Channel Velocimeter, Millar
Instruments, Inc) was placed in the LAD, its proximal lumen being
placed in the midportion of the artery by use of injection of contrast
medium. Position was adjusted to obtain an optimal audio signal and
phasic tracing of coronary flow velocity. The use of this device to
assess intracoronary flow velocity has been discussed in
detail.5 Heart rate, aortic pressure (through the guiding
catheter), mean and phasic flow velocities (kilohertz shift), and ECG
were monitored continuously throughout the protocol.
Flow-dependent coronary dilatation was assessed by injecting a bolus of 10 mg papaverine (8 mg papaverine/mL, 0.9% saline) in the midportion of the LAD through the proximal lumen of the Doppler catheter and measuring the diameter of the proximal LAD (LAD1); the proximal circumflex artery (LCx) segment served as control. The dose of papaverine was chosen on the basis that maximal flow is achieved by a bolus of 12 mg papaverine injected into the left main artery.8 Papaverine reflux, which might have caused direct dilatation of the LAD1, was excluded by verifying that injection of a bolus of 2 mL contrast through the Doppler catheter did not cause dye reflux to the LAD1. Angiograms were performed with an injection of 8 mL of low-osmolarity contrast medium (meglumine ioxaglate) at baseline and 60 seconds after the peak flow velocity induced by papaverine, this time corresponding to the time course of maximal flow-dependent dilatation observed in conscious dogs.9 10 Flow velocity was measured in the distal LAD (LAD2), near the tip of the Doppler catheter, just before each angiogram so as to avoid the hyperemic effect of the contrast material. Measurements of LAD1, LAD2, and LCx diameters were made on each angiogram. Serial injections of the left coronary artery were performed at intervals of at least 5 minutes to exclude contrast-induced dilatation.11 Last, coronary angiography was repeated 4 minutes after intracoronary infusion of 2 mg isosorbide dinitrate (ISDN) through the guiding catheter.
Estimates of
blood flow (F) in LAD2 was calculated from measurements of
mean coronary flow velocity in LAD2 (v) and LAD2 cross-sectional area
(CSA): F=vxCSA. Cross-sectional area was calculated from
measurements
of LAD2 diameter (d) assuming a circumferential model:
CSA=
d2/4.
Quantitative Coronary Arteriography
Coronary arteriograms
were obtained by ECG-triggered digital
subtraction at a rate of six frames per second on a 512-pixel matrix
(General Electric CGR DG 300). The angiographic system was set up in
the right anterior oblique position with adequate cranial or caudal
angulation to allow optimal view of the LAD1, LAD2, and LCx segments on
end-diastolic frames without overlap by side branches.
Relations between focal spot, patient, and height of image tube were
kept constant during the protocol. Analysis of angiograms was performed
by a previously validated technique.5 12 Briefly, the
reliability and accuracy of the method have been previously established
on empty catheters and on calibrated contrast medium–filled catheters.
About three diameters were determined by millimeter length, and an
averaged value representing the mean reference diameter was
provided for the whole segment. The accuracy of the technique was
3.6±0.5% (mean±SD), and the precision was 2.4±0.9%. The
maximum
error between the actual and the calculated diameter was equal to
±5.7% (R2=.994). In this study, a segment of
the guiding catheter positioned in the left main coronary artery and
filled with saline was placed close to the center of the image and was
used as a scaling device for calibration before the beginning of the
procedure. Segments 6 to 10 mm long (18 to 30 diameter measurements) of
the LAD1, LAD2, and LCx were analyzed. Each segment was defined with
two anatomic references to reproducibly measure the same segment after
each injection. All diameter measurements were corrected by a
magnification factor, taking into account the distance of the segment
from the center of the image. Each angiogram was analyzed at random
without knowledge of the protocol sequence (base, papaverine, and
ISDN).
Statistical Analysis
All data are expressed as
mean±SEM. Differences between the two
groups of patients for clinical and biological characteristics and
basal hemodynamic and echocardiographic parameters were compared by the
nonparametric Mann-Whitney test. Statistical comparisons of hemodynamic
parameters, coronary vessel diameters, and coronary velocity and flow
under base, papaverine, and post-ISDN conditions were made by two-way
ANOVA with repeated measures for experimental condition factor,
followed by the Fisher protected least-significant-difference test.
Statistical significance was assumed if the null hypothesis could be
rejected at the .05 probability level.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Patient Characteristics
The sex ratio, age, and basal heart rate were comparable in the two groups (Table
). On the basis of selection, mean
aortic pressure was significantly higher in hypertensive patients
(P<.001) than in control subjects. Echocardiography showed
similar left ventricular end-diastolic diameter and
fractional shortening in the two groups and significantly higher septal
and posterior wall thicknesses and left ventricular mass index in
hypertensive patients than in control subjects. Left ventricular mass
index was within normal range in 10 of 14 hypertensive patients and was
slightly elevated in 4. Lipid profile was similar in the two
groups.
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Hemodynamic Effects of Intracoronary Papaverine and ISDN
Infusion
In control subjects, papaverine and ISDN increased heart rate
by
5±2 beats per minute (P<.01) and by 8±1 beats per
minute
(P<.001), respectively, and reduced mean arterial pressure
by 8±2 mm Hg (P<.01) and by 8±2 mm Hg
(P<.01), respectively. In hypertensive patients, papaverine
and ISDN increased heart rate by 5±2 beats per minute
(P<.05) and by 7±1 beats per minute (P<.01),
respectively, and reduced mean arterial pressure by 12±3 mm Hg
(P<.001) and by 20±3 mm Hg (P<.001),
respectively.
Flow-Dependent and ISDN-Mediated Diameter Changes of Epicardial
Coronary Arteries
In both control subjects and hypertensive patients,
the injection
of papaverine caused a significant increase in mean LAD2 diameter (Fig
1) and LAD2 blood flow velocity (287±24% and
346±29%
in control subjects and hypertensive patients, respectively). This
resulted in a significant and comparable increase in the estimate of
coronary blood flow in LAD2 (521±41% and 406±32% in control
subjects and hypertensive patients, respectively) (Fig 1).
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Mean basal diameter of LAD1 was comparable in the two groups (Fig
2). In all control subjects, the injection of papaverine
in the midportion of the LAD caused dilatation of the LAD1 segment
exposed to increased flow, indicating flow-dependent coronary
dilatation. The mean LAD1 diameter increased 17.0±3.3%
(P<.001) (Fig 2). In contrast, the diameter of the
LCx
control segment did not change (2.92±0.16 mm at base versus
2.91±0.15
mm after papaverine), showing that the dilatation observed in the LAD1
was not due to contrast medium or to reflux of papaverine. In all
hypertensive patients, no LAD1 segment dilated in response to increased
flow (mean change in LAD1 diameter, -0.4±0.6%, NS) (Fig
2), showing
no flow-dependent coronary dilatation.
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After ISDN infusion, the mean
increase in LAD1 diameter was comparable
in the two groups (Fig 2
), showing a similar dilative
capability
(30.0±4.1% and 21.9±1.9% in control subjects and hypertensive
patients, respectively).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study shows that flow-dependent dilatation in angiographically normal coronary arteries is lost in patients with hypertension, whereas the capability of the artery to dilate in response to ISDN, an endothelium-independent vasodilator, is preserved.
Flow-dependent dilatation was first demonstrated in the canine femoral artery13 and then reported in coronary arteries of animals.9 10 It has also been shown in humans with normal epicardial coronary arteries.3 4 We also observed in our control group a flow-dependent coronary dilatation that was not caused by retrograde diffusion of papaverine. Indeed, in the arteries of hypertensive patients, the finding that there was no dilatation of the proximal segment of the LAD, whereas the distal segment dilated during papaverine injection, also argues against reflux of papaverine. The present study was the first one assessing the coronary flow–mediated response in patients with essential hypertension, no other risk factors of atherosclerosis, and angiographically normal coronary arteries.14 In contrast to the loss of flow-mediated vasodilatation observed in epicardial coronary arteries in this study, another study has shown that coronary flow–mediated dilatation is preserved in patients with hypertension and other risk factors for atherosclerosis.15 The discrepancy between our study and that by Anderson et al15 may be related to the severity of hypertension. Patients studied by Anderson et al had mild hypertension (mean blood pressure, 153/84 mm Hg), whereas patients we studied had more severe hypertension (mean blood pressure, 173±3/107±3 mm Hg).
Previous studies demonstrated that flow-mediated dilatation was impaired in systemic arteries of monkeys with early atherosclerosis16 and of subjects with risk factors for atherosclerosis before anatomic evidence of disease.17 Different responses to flow increase with different early stages of atherosclerosis have been reported. Nabel et al18 showed a loss of flow-mediated dilatation in patients with atherosclerosis. Zeiher et al19 demonstrated that flow-dependent coronary dilatation was preserved in patients with hypercholesterolemia and angiographically smooth arteries as well as in angiographically normal arteries in patients with atherosclerosis elsewhere in the coronary circulation. Nevertheless, it is unlikely that early atherosclerosis, which may be present despite normal coronary arteriography,20 can explain the loss of flow-mediated dilatation observed in all the 14 hypertensive patients we studied, with no other risk factors or angiographic sign of atherosclerosis elsewhere in the coronary vasculature. Differences in the response to increased flow between systemic and coronary arteries may exist in hypertensive patients, since flow-dependent dilatation in brachial arteries has been shown to be preserved.21
Flow-dependent dilatation is mediated by the endothelium9 through the release of endothelium-derived relaxing factor,22 identified as nitric oxide (NO).23 Hyperpolarizing factor may also contribute to flow-dependent vasodilatation.24 The endothelium also mediates vasodilatation to receptor stimuli through the release of NO, and abnormal receptor-mediated endothelium-dependent dilatation of the coronary arteries, assessed by the response to acetylcholine, has been demonstrated in hypertensive patients.1 Thus, there is a complete loss of the endothelium-mediated vasodilatation in epicardial coronary arteries of hypertensive patients. Panza et al25 showed a reduced activity in the NO system in the peripheral vasculature of hypertensive patients that was not related to decreased availability of substrate for NO synthesis,26 but possibly due either to reduced synthesis, release, or diffusion of NO to vascular smooth muscle or to the capacity of the endothelial cell to take up the substrate for the synthesis of NO. However, the effect of an endothelium-derived contracting substance cannot be excluded.
Flow-mediated dilatation of coronary arteries may contribute to the normal physiological response during sympathetic stimulation. Indeed, flow-mediated dilatation has been demonstrated when myocardial metabolic demand increases.27 In addition, the functional integrity of the endothelium is a major determinant of epicardial coronary artery vasodilatation during sympathetic stimulation by the cold pressor test.28 The loss of the flow-dependent dilatation of coronary arteries in hypertensive patients may thus be one of the mechanisms that participate in the abnormal vasoconstriction we have demonstrated in hypertensive patients in response to the cold pressor test.5
Conclusions
Our results indicate that flow-dependent
dilatation of
epicardial coronary arteries is abolished in hypertensive patients.
This loss may impair normal dilatation during sympathetic stimulation.
In addition, by keeping low shear stress, flow-mediated dilatation may
protect the endothelial cells from damage by exposure to high shear
stress.29
Received October 17, 1994; revision received January 4, 1995; accepted January 5, 1995.
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M. Kozakova, C. Palombo, L. Pratali, G. Pittella, F. Galetta, and A. L'Abbate Mechanisms of Coronary Flow Reserve Impairment in Human Hypertension: An Integrated Approach by Transthoracic and Transesophageal Echocardiography Hypertension, February 1, 1997; 29(2): 551 - 559. [Abstract] [Full Text]
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