(Circulation. 1997;96:1513-1519.)
© 1997 American Heart Association, Inc.
Articles |
Vitamin C Improves Endothelial Dysfunction of Epicardial Coronary Arteries in Hypertensive Patients
From the Medical Clinic, Department of Cardiology, University of Freiburg, Germany.
Correspondence to Ulrich Solzbach, MD, Medizinische Klinik III, Abteilung Kardiologie, Universität Freiburg, Hugstetterstr 55, D-79106 Freiburg, Germany.
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Abstract |
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Background There is evidence for increased formation of free radicals in patients with hypertension, raising the possibility that NO is inactivated by free radicals, which impairs coronary endothelial function. Therefore, we tested the hypothesis that the antioxidant vitamin C could improve abnormal endothelial function of coronary arteries in patients with hypertension.
Methods and Results In 22 hypertensive patients without relevant coronary artery stenoses, endothelium-dependent vascular responses of the left anterior descending coronary artery (LAD) to acetylcholine (0.01, 0.1, and 1.0 µmol/L) were determined before and immediately after intravenous infusion of 3 g vitamin C (17 patients) or placebo (5 patients). In a subgroup of 10 patients, papaverine-induced flow-dependent vasodilation (FDD) was measured before and after vitamin C (5 patients) or placebo (5 patients) infusion. Segmental responses of the coronary artery luminal area were analyzed with quantitative coronary angiography. Before vitamin C infusion, the mean changes of LAD luminal areas at increasing doses of acetylcholine were -6.1±2.2%, -15.2±4.9%, and -33.9±8.1% (negative numbers symbolize vasoconstriction) and during FDD, 5.4±1.0%. The vasoconstrictor response during acetylcholine was reduced and FDD was augmented by vitamin C. After vitamin C infusion, LAD luminal areas changed by -3.2±2.3%, -5.8±3.6%, and -10.2±5.6% (P<.05, acetylcholine) and 17.8±2.8% (P<.05, FDD). Doppler flow velocity (during baseline, acetylcholine, and FDD) was not significantly affected by vitamin C.
Conclusions Vitamin C improves the endothelium-dependent vasomotor capacity of coronary arteries in patients with hypertension and patent coronary arteries. These findings suggest that increased oxidative stress contributes to endothelial dysfunction in hypertensive patients.
Key Words: endothelium • blood flow • acetylcholine • antioxidants
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Introduction |
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The vascular endothelium plays an important role in the regulation of the vasomotor tone of the coronary arteries, mainly by the synthesis and release of vasoactive substances1 such as endothelium-derived relaxing factor,2 which has been identified as NO.3 Endothelium-derived relaxing factor is released after the stimulation of muscarinic receptors on endothelial cells by acetylcholine4 as well as other physical stimuli.5 Abnormalities in the coronary vasomotor response to acetylcholine have been observed in patients with atherosclerosis,6 hypercholesterolemia,7 diabetes mellitus,8 cigarette smoking,9 or essential hypertension.10 11
The exact mechanism of endothelial dysfunction in patients with atherosclerosis and coronary risk factors is not yet known. Numerous mechanisms have been suggested. They include an increased diffusional barrier for NO due to intimal cell proliferation and lipid deposition,12 L-arginine depletion,13 altered endothelial cell receptor coupling mechanism,14 and inactivation of NO by superoxide anions15 16 or oxidized LDLs.17 18 Recently, several studies have shown strong evidence that inactivation of NO by increased vascular superoxide or other radicals could account for endothelial dysfunction in human forearm circulation: The antioxidant vitamin C was reported to improve impaired endothelium-dependent vasodilation of the brachial artery in patients with diabetes,19 cigarette smoking,20 and coronary artery disease.21
Thus, the primary objective of this study was to determine whether observations made in animal studies and in the human brachial artery could be extended to the human coronary arteries. We hypothesized that endothelial dysfunction of the epicardial coronary arteries in patients with arterial hypertension might be improved by vitamin C. We have examined acetylcholine-induced vascular responses and papaverine-induced FDD in the coronary circulation of patients with hypertension before and after administration of vitamin C.
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Methods |
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Patient Population
The study population included 22 patients with a known history of essential hypertension for at least 5 years. Each patient had a well-established history of chronically elevated blood pressure (
150/95 mm Hg) without any apparent underlying cause. All
patients were undergoing routine diagnostic cardiac
catheterization for evaluation of chest pain (serial
cases). A prerequisite for inclusion in the study was the absence of
hemodynamically significant stenoses in the
coronary arteries. Sixteen patients had angiographically
normal, smooth-appearing coronary arteries. Six patients had
minor luminal irregularities in the left circumflex coronary
artery or in the right coronary artery but an angiographically
normal LAD (the vessel under study). The left ventricular
cineangiograms of all patients showed no evidence of left
ventricular hypertrophy or segmental wall
motion abnormalities. Patients with a history of unstable angina or
recent myocardial infarction; a clinical history suggestive of variant
angina or valvular heart disease; clinical evidence of heart
failure, diabetes mellitus, or
hypercholesterolemia; and a history of
cigarette smoking during the previous 6 months were excluded. All
patients gave written informed consent before the study. The study was
approved by the local Ethics Committee of the University of
Freiburg.
Study Protocol
All vasoactive medications, including calcium channel blockers,
ACE inhibitors, long-acting nitrates, ß-adrenergic
blockers, or antioxidant drugs were withheld at least 48 hours before
cardiac catheterization. Because of suspected
coronary heart disease, all patients were taking aspirin (100
mg/d) at the time of the study. Diagnostic left-side
heart catheterization and coronary angiography
were performed with a standard percutaneous femoral
approach. After completion of the diagnostic
catheterization, an additional bolus of 10 000 U
heparin was given intravenously, and an 8F guiding catheter
was used to cannulate the left main coronary artery. A 2.7F
infusion catheter was then advanced over a 0.014-in Doppler flow
velocity guidewire (Cardiometrics, Inc) into a nonbranching segment of
the proximal part of the LAD. For the purpose of this study, the tip of
the Doppler guidewire was positioned 
1 cm distal to the tip of
the 2.7F infusion catheter. The 0.014-in guidewire contains at its tip
a 12-MHz pulsed Doppler ultrasound velocimeter
(FlowMAP, Cardiometrics, Inc). The position of the tip of the
Doppler guidewire was carefully chosen to obtain a stable velocity
signal and was cineangiographically documented with each injection of
contrast material. Doppler flow velocity (maximum velocity and
average peak velocity) was recorded continuously throughout the
study protocol.
After stable conditions were obtained, acetylcholine was selectively infused into the LAD via the infusion catheter to assess endothelium-dependent vasomotor responses of the LAD. Increasing doses of acetylcholine were used to achieve estimated final acetylcholine concentrations in the coronary bed of 0.01, 0.1, and 1.0 µmol/L (assuming blood flow in the LAD of 80 mL/min) at an infusion rate of 1.6 mL/min, lasting 3 minutes for each concentration. In a subgroup of 10 patients, endothelium-mediated FDD was measured 10 minutes after the end of acetylcholine infusion. For that purpose, 7 mg papaverine was selectively infused into the LAD through the 2.7F infusion catheter to maximally increase blood flow in the territory of the LAD. Previous studies22 23 demonstrated that the dose of 7 mg papaverine, subselectively infused into the LAD, elicits a maximal increase in coronary blood flow without affecting global hemodynamic parameters. Eighty seconds after papaverine had induced an increase in blood flow, a coronary angiogram was obtained to measure the diameter of the proximal segment of the LAD exposed to increased blood flow but not directly to papaverine itself. Reflux of papaverine into the proximal LAD segment was excluded by power injection of contrast material through the infusion catheter.
After baseline conditions were obtained, 3 g vitamin C (sodium ascorbate, Merck, dissolved in 100 mL 0.9% saline) was administered intravenously over 10 minutes. In 5 of those patients who received acetylcholine and papaverine infusions, 100 mL 0.9% saline solution (placebo) was infused without vitamin C. The total dose of vitamin C was chosen to reach or surpass estimated systemic blood concentrations that have shown beneficial effects in previous human forearm studies19 20 and inhibition of superoxide anion–mediated peroxidation.24
After infusion of vitamin C, intracoronary infusions of increasing doses of acetylcholine were repeated under the same protocol as described above. Finally, after a 5-minute recovery period, 0.2 mg nitroglycerin was injected into the left main stem via the guiding catheter to assess endothelium-independent vasodilator capacity of the epicardial artery. As in previous studies,22 the intracoronary infusions of acetylcholine, papaverine, and nitroglycerin did not significantly affect heart rate and blood pressure.
In a subgroup of 12 patients, we examined the effects of intracoronary infusion of acetylcholine (first study of the protocol). In another subgroup of 5 patients, the effects of acetylcholine and papaverine (FDD) were tested (second study of the protocol), and in a third subgroup of 5 patients, the effects of acetylcholine and papaverine (FDD) were analyzed before and after placebo instead of vitamin C (third study of the protocol). Throughout the study, heart rate and aortic pressure were continuously measured via the guiding catheter. Serial manual injections of nonionic contrast material were performed during the control period, at the end of each acetylcholine infusion, at recontrol after acetylcholine infusion, after papaverine infusion, and after injection of nitroglycerin.
Quantitative Coronary Angiography
The method of quantitative coronary angiography has been
described in previous studies from our
institution.6 22 23 25 Quantitative angiography was used
to assess the dimensions of the epicardial artery and to determine
cross-sectional area of the artery immediately distal to the radiopaque
tip of the Doppler guidewire to convert the Doppler-derived
flow velocity to an estimate of coronary arterial
blood flow. Coronary angiography was performed by use of a
simultaneous biplane multidirectional isocentric x-ray
system (Siemens Bicor). The coronary arteries under study
were positioned near the isocenter, and special care was taken to avoid
overlapping of coronary segments. Biplane
cineangiograms were recorded at a frame rate of 12.5
frames per second in the 12-cm field of view. For quantitative
analysis, end-diastolic cine frames were
videodigitized and stored for subsequent computer analysis in
the image analysis workstation (512x512 matrix size, with an
eight-bit gray scale).
Quantitative coronary angiography by automatic contour detection of the coronary artery was performed by a geometric edge differentiation technique. Calculation of the exact radiological magnification factor of the measured segment was used to scale the data from pixels to millimeters as previously described.26 The accuracy and precision of this technique as well as the reproducibility of serial measurements under routine clinical conditions have been established in previous studies.6 22 23 25
In all 22 patients, quantitative measurements were performed in a distinct 4- to 8-mm-long relatively straight LAD segment distal to the tip of the Doppler guidewire. The cross-sectional area at this vessel segment was measured to analyze the acetylcholine-induced coronary vasomotor response. Furthermore, the measured luminal area was used for a rough estimation of coronary artery blood flow in the proximal LAD by multiplying the cross-sectional area by the mean Doppler flow velocity. In those patients (n=10) who received acetylcholine and papaverine infusions, an additional segment in the more proximal part of the LAD was measured. This segment was exposed to increased blood flow but not directly to papaverine itself. Tapered or tortuous segments were not used. The same LAD segments were analyzed before and after vitamin C administration. In all patients, measurements of corresponding segments of interest were performed in both views of the biplane images with the radiopaque tip of the Doppler guidewire and the takeoff of side branches used as anatomic landmarks for identification of corresponding vessel segments. The vessel's cross-sectional area was calculated from both views assuming an elliptical shape. Because of the selection criteria for LAD segments, the LAD segments finally analyzed were not always the most constricting segments in the vessel.
Statistical Analysis
All data are given as mean±SEM. Comparisons of the
acetylcholine- and papaverine-induced vascular responses before and
after infusion of vitamin C or placebo were analyzed by
Student's paired t test. The vitamin C group was compared
with the placebo group by an unpaired t test. The
relationship between the vasoconstriction during maximal acetylcholine
dose before vitamin C infusion and the improvement after vitamin C
(difference between the vascular responses before and after vitamin C)
was examined by regression analysis. Statistical significance
was accepted if the null hypothesis could be rejected at the
P<.05 level.
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Results |
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Clinical Characteristics and Baseline Measurements
Twenty-two patients with a mean age of 55±9.6 years (range, 32 to 75 years) were enrolled in the study. Of these, 13 were women and 9 were men. All patients had a history of arterial hypertension for at least 5 years. No patient had a history of hypercholesterolemia, diabetes mellitus, cigarette smoking, or any other systemic disease predisposing them to endothelial dysfunction. The mean aortic blood pressure during catheterization was 110±6.5 mm Hg, the left ventricular end-diastolic pressure was 9±3.7 mm Hg, and the mean heart rate was 77±15 bpm. Mean arterial blood pressure and heart rate did not change by the acetylcholine and papaverine infusion. Furthermore, there were no differences in the hemodynamic parameters before and after administration of vitamin C or placebo.
Responses of Epicardial Arteries to Acetylcholine Before and After
Vitamin C Administration
During the first study of the protocol, a total of 12 LAD segments
(12 patients) distal to the tip of the Doppler guidewire were
analyzed. Increasing concentrations of acetylcholine
dose-dependently decreased the luminal areas of the coronary
segments under study (Fig 1
and
Table). The vasomotor response to peak
dose of acetylcholine varied from 15% dilation to 68%
arterial constriction compared with baseline dimensions
(Fig 2). The vasomotor response to
acetylcholine was found to be a local phenomenon, with segmental
variations of major and minor vasoconstrictions in different segments
of the LAD from the same patient. This segmental vasoconstriction in
response to acetylcholine was ameliorated by vitamin C. The mean
arterial constriction improved significantly at medium and
peak dose of acetylcholine, from -15.2±4.9% to -5.8±3.6% and
-33.9±8.1% to -10.2±5.6% before and after vitamin C
administration at 0.1 and 1.0 µmol/L acetylcholine
concentration, respectively (P=.05). The
endothelium-independent vasodilator
nitroglycerin dilated the segments by 34.1±5.2%.
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Fig 2
demonstrates the individual changes in luminal areas of all
analyzed coronary segments to increasing doses of
acetylcholine before and after vitamin C infusion and after
nitroglycerin. The control angiograms under baseline
conditions after acetylcholine infusion (C2 in Fig 2)
showed no significant change in luminal area compared with the initial
baseline control (C1 in Fig 2). The subsequent vitamin C
infusion did not reveal a significant change in mean luminal area under
baseline conditions at the subsequent control angiograms
(C3 in Fig 2). However, the acetylcholine-induced
vasoconstriction was significantly reduced after vitamin C infusion. In
those patients who received vitamin C (17 patients, first and second
study of the protocol), the extent of improvement of the
acetylcholine-induced vasoconstriction (during maximal acetylcholine
dose) after vitamin C treatment correlated with the pretreatment
vasoconstrictor response (r=.83, P<.05),
confirming our observation that patients with an impaired vascular
response before vitamin C infusion demonstrated improvement after
vitamin C treatment.
Responses of Epicardial Arteries to Acetylcholine and Papaverine
(FDD) Before and After Vitamin C/Placebo Administration
During the second and third studies of the protocol, 10 LAD
segments distal to the tip of the Doppler guidewire and 10
additional segments in the proximal part of the LAD (for
papaverine-induced FDD) were analyzed. Five patients received
vitamin C (second study), and 5 received placebo (third study). In the
patients of the second study, the LAD segments showed similar responses
to increasing doses of acetylcholine, as observed during the first
study with a significantly reduced vasoconstriction after vitamin C
infusion (Fig 3 and Table). In addition,
papaverine-induced FDD was significantly increased after vitamin C
infusion. The mean arterial FDD improved from 5.4±1.0%
before vitamin C infusion to 17.8±2.8% after vitamin C infusion
(P<.05). Furthermore, the changes in luminal area during
peak dose of acetylcholine and at FDD after vitamin C infusion were
significantly different from placebo values (Fig 3 and Table). The mean
changes in luminal area at peak dose of acetylcholine were
-15.4±3.0% after vitamin C infusion compared with -34.5±7.1%
after placebo infusion (P<.05). The mean changes in luminal
area at FDD were 17.8±2.8% after vitamin C infusion compared with
6.2±0.8% after placebo infusion (P<.05). In contrast to
the endothelium-dependent vascular responses, the
endothelium-independent vasodilation after
nitroglycerin was not affected by vitamin C (Fig 3). In
the placebo group (third study), acetylcholine-induced vasoconstriction
as well as FDD showed similar values before and after placebo infusion
(see Table).
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Responses of Coronary Blood Flow to Acetylcholine and
Papaverine Before and After Vitamin C/Placebo Administration
The coronary blood flow increased dose-dependently in
response to acetylcholine (17 patients, first and second study) and
papaverine (5 patients, second study). Compared with the mean blood
flow during baseline conditions, acetylcholine increased the mean
coronary blood flow by 22±8%, 60±25%, and 125±65% at
corresponding doses of acetylcholine infusion, respectively. The mean
blood flow after papaverine infusion increased to 275±120% of the
baseline value. The mean increases in coronary blood flow were
similar before and after vitamin C infusion (Fig 4). Furthermore, in the placebo group
(third study), no significant difference could be found in the mean
increases of coronary blood flow before and after placebo
infusion. In particular, there was no significant difference in the
mean papaverine-induced increases of coronary blood flow before
and after vitamin C or placebo. Because we did not observe significant
changes in mean arterial pressure and heart rate, the
vascular resistance of the coronary circulation was not
significantly changed by the administration of vitamin C.
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Discussion |
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The present study is the first to demonstrate that impaired endothelium-dependent vasodilatory function in the human coronary arteries can be improved by the administration of the antioxidant vitamin C. In a homogeneous group of 22 patients with essential hypertension and no further risk factors or systemic diseases predisposing to endothelial dysfunction, we found that vasoconstriction of epicardial coronary arteries during intracoronary infusion of acetylcholine, representing endothelial dysfunction,6 11 was significantly improved after vitamin C infusion. Furthermore, endothelium-mediated FDD was increased dramatically after vitamin C infusion. Our findings suggest that increased oxidative stress contributes to endothelial dysfunction in the coronary circulation of patients with hypertension.
The endothelium is a very important modulator of vasomotor tone and function through the synthesis and release of endothelium-derived NO.2 The coronary vascular response to acetylcholine depends on the integrity of the endothelium and the endothelium-derived NO pathway.4 6 The FDD is another tool to identify endothelial dysfunction.22 23 25 The precise mechanism responsible for endothelium-derived dysfunction of the coronary arteries in patients with known risk factors for coronary atherosclerosis is not well understood, but one possibility is increased inactivation of endothelium-derived NO by oxygen-derived free radicals.27 28 29 Epidemiological studies have suggested an association between increased intake of antioxidant vitamins and reduced risk of coronary artery disease.30 31 32 33 One previous study failed to demonstrate a beneficial effect of vitamin C on endothelial vasodilator function of forearm vessels in hypercholesterolemic patients in response to intra-arterial acetylcholine.34 But most recently, beneficial effects of vitamin C on endothelial vasomotor dysfunction in forearm vessels in patients with diabetes,19 cigarette smoking,20 and coronary artery disease21 have been reported. Vitamin C, or ascorbic acid, is a strong reducing agent known to act as an antioxidant in vitro and in vivo.24 It very effectively protects lipids in human plasma against peroxidative damage by scavenging oxygen-derived free radicals,35 and it plays an important role in the regulation of intracellular redox state through its interaction with glutathione.36
There is also evidence from animal studies that an excess of superoxide radicals in the arterial vascular bed could account for the depressed acetylcholine-induced vasodilation in arterial hypertension. In a study with genetically hypertensive rats, Grunfeld et al37 demonstrated that the major reason for the deficit in NO concentration is that although the rate of production is nearly normal, it is scavenged as it is produced by excess superoxide anions. The authors showed that the treatment of endothelial cells with SOD increased NO release. Vega et al38 reported that SOD is reduced in aortas of rats with renal hypertension. Ito et al39 found that SOD is reduced in the myocardium of genetically hypertensive rats. Although it has not yet been shown in human coronary arteries, abnormal endothelial concentration of SOD, the endogenous pathway for the disposal of superoxide radicals, could play one important role in the regulation of vasomotor tone and therefore be responsible for increased inactivation of endothelial NO in patients with hypertension. In another study, Chen et al40 demonstrated that SOD activity was depressed in neutrophils and red blood cells from patients with pregnancy-induced hypertension. However, in a study in the forearm vasculature of hypertensive patients and healthy control subjects, Gracia et al41 could not demonstrate an improvement in the impaired acetylcholine-mediated endothelium-dependent responses after copper-zinc SOD administration. Hence, these data on the brachial circulation do not support the hypothesis of increased extracellular superoxide anion–mediated destruction of NO as the mechanism that accounts for impaired endothelium-dependent vascular relaxation in essential hypertension.
In addition to the decreased NO activity, abnormal production of several vasoactive substances has been suggested to be responsible for the impaired endothelium-dependent vasodilation in hypertension.42 43 44 Several studies have suggested that Ang II might play a direct role in vascular remodeling in hypertension.45 46 47 Recently, it was demonstrated from data on rabbit aorta that transmural pressure results in a net Ang II production from vascular cells via the local renin-angiotensin system.48 Interestingly, Ang II has been suggested to activate enzyme systems that promote superoxide generation in vascular smooth muscle cells.49 It is not known whether Ang II would produce a similar effect in the endothelium. Nevertheless, it is interesting to speculate that this pathophysiological pathway could also contribute to increased oxidative stress in the coronary endothelium in hypertensive patients. Regardless of the exact mechanism of increased inactivation of NO within the endothelial wall layer, our observations strongly support the concept that increased production and/or activity of oxygen-derived free radicals contribute to endothelial dysfunction of coronary arteries in patients with hypertension.
We found that the microcirculatory resistance did not change significantly before and after vitamin C infusion. A possible reason for this observation could be that in patients with hypertension, endothelial dysfunction of the coronary circulation is confined to the large epicardial arteries rather than to the resistance vessels. In that case, acetylcholine-induced vasoconstriction and the possible improvement by antioxidant vitamin C can be anticipated in epicardial arteries but not in the coronary resistance vessels. This is in line with results of a recent study by Zeiher et al,6 who found no apparent effect on coronary blood flow responses to acetylcholine in patients with a history of hypertension. Interestingly, previous studies in the human forearm circulation in patients with hypertension showed impaired blood flow responses to acetylcholine.10 These discrepancies might simply be related to the different vascular beds. Whereas large arteries like the epicardial arteries, as well as cerebral and limb arteries, are often diseased in hypertension, hypertensive vascular disease rarely develops in the large vessels of the human brachial arteries. In a recently published study, Egashira et al50 concluded from their data that diminished endothelium-dependent dilation of epicardial coronary vessels in hypertensive patients may be related to a selective abnormality in the muscarinic receptor of the endothelium and that blunted endothelium-dependent dilation of the resistance coronary artery in hypertensive patients may be related to a more generalized endothelial abnormality but not confined to the muscarinic receptor. In that case, one could hypothesize that the beneficial effect of antioxidant vitamin C on impaired acetylcholine-induced vasodilation (mediated by muscarinic receptors) in patients with hypertension should be expected predominantly in the epicardial vessels, as we found in our study.
In the present study, we did not include "normal" control subjects or patients referred for coronary angiography without coronary artery disease and without risk factors known to affect endothelial function, including hypertension. Therefore, the effect of vitamin C on the coronary vasculature in normal control subjects during acetylcholine or papaverine infusion is not yet known. But there is evidence from the findings in the forearm model that vitamin C had no effect on the vasculature in normal control subjects: The recently published studies on the effect of vitamin C on the endothelial function in the forearm artery demonstrated that vitamin C did not change the vasodilator responses of the brachial circulation to methacholine19 or acetylcholine20 in normal control subjects.
In summary, acute administration of the antioxidant vitamin C in a physiological dose significantly improved endothelial vasomotor dysfunction of the epicardial arteries in patients with hypertension. The vascular resistance of the coronary circulation was not altered before and after vitamin C infusion. Our findings strongly suggest that increased oxidative stress contributes to abnormal endothelial function in patients with hypertension. Further studies examining the long-term effect of antioxidant vitamin C supplementation on cardiovascular function will be required before vitamin C supplementation can be recommended.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We thank the nurses of the Cardiac Catheterization Laboratory at the University of Freiburg for invaluable assistance in the performance of this study.
Received January 15, 1997; revision received April 8, 1997; accepted April 12, 1997.
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