(Hypertension. 1997;30:50-56.)
© 1997 American Heart Association, Inc.
Articles |
Basal Release of Nitric Oxide Is Decreased in the Coronary Circulation in Patients With Heart Failure
From the Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University, Faculty of Medicine, Fukuoka, Japan.
Correspondence to Masahiro Mohri, MD, PhD, Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University, Faculty of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan. E-mail mmohri{at}cardiol.med.kyushu-u.ac.jp
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Abstract |
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Abstract It is unknown whether basal release of endothelium-derived nitric oxide in the coronary artery is altered in heart failure in humans. The aim of the present study was to evaluate the effect of inhibition of nitric oxide synthesis on basal tone of the conduit and resistance coronary arteries in awake patients. Coronary blood flow velocity (Doppler guide wire) and coronary arterial diameter (quantitative coronary angiography) were measured in 14 patients with heart failure caused by nonischemic left ventricular dysfunction (7 idiopathic dilated cardiomyopathy and 7 valvular insufficiency) and 7 patients with normal ventricular function (controls). Intracoronary NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, at graded doses decreased coronary blood flow in both groups. However, the magnitude of flow reduction was smaller in patients with heart failure than in control patients (P<.0001). The magnitude of coronary blood flow reduction in response to L-NMMA inversely correlated to indexes of left ventricular contractile function (P<.01) but was not affected by the cause of heart failure. Constriction of the large epicardial coronary artery with L-NMMA also tended to be attenuated in patients with heart failure. In summary, vasoconstricting response to L-NMMA was blunted in the coronary resistance artery in heart failure in vivo. These findings suggest that basal release of nitric oxide in the coronary circulation is decreased in patients with heart failure.
Key Words: nitric oxide • heart failure, congestive • coronary circulation • cardiomyopathy, congestive • heart valve diseases
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Introduction |
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Endothelium-derived nitric oxide (NO) is an endogenous potent vasodilator that is released from vascular endothelial cells in response to various vasoactive substances as well as mechanical shear stress exerted on the endothelial cell.1 2 3 Since its discovery, the role of NO in regulating blood flow under physiological and pathological conditions such as hypercholesterolemia4 and hypertension5 has been vigorously investigated.
As for congestive heart failure (CHF), Habib et al6 reported that systemic administration of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) caused systemic vasoconstriction, as evidenced by increased vascular resistance, in patients with heart failure and that this response was greatest in those with highest basal resistance. In the forearm circulation, the constricting response to intra-arterial L-NMMA in heart failure patients was reportedly similar or even enhanced compared with control patients.7 8 This evidence would suggest that basal release of NO is at least preserved and plays a substantial role in the peripheral circulation with heart failure. However, NO synthesis and its contribution to basal arterial tone may be heterogeneously affected in different vascular territories in heart failure.9 10
Whether basal or agonist-mediated release of NO in the coronary
circulation is affected in CHF remains to be determined. Data obtained
in animal experiments are inconsistent regarding the functional
role of NO in regulating coronary blood flow in heart failure.
O'Murchu and coworkers9 demonstrated that
coronary artery rings from dogs with pacing-induced heart
failure showed enhanced dilator responses to
2-adrenergic agonists that were mediated by NO. In
contrast, Wang et al11 observed depressed NO-mediated
controls of the coronary circulation in dogs with heart failure
as evidenced by attenuated dilation of the large epicardial
coronary artery in response to brief coronary occlusion
and acetylcholine. However, no study has evaluated the
physiological role of NO in the regulation of
coronary blood flow in patients with heart failure under either
baseline or stressed conditions. Thus, in the present study we
aimed to elucidate the role of basally released NO in the control of
coronary blood flow in patients with CHF caused by
noncoronary artery disease. To achieve this, we examined the
effects of intracoronary administration of a specific
inhibitor of NO synthesis, L-NMMA, on coronary
blood flow and diameter in patients with heart failure and control
patients.
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Methods |
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Subjects
Fourteen patients with heart failure caused by nonischemic left ventricular dysfunction (mean age, 57±11 years; 8 men and 6 women; CHF group) were studied (Table 1
). The cause of left ventricular
dysfunction was idiopathic dilated cardiomyopathy
in 7 patients (DCM group; patients 1 through 7 in Table 1) and
volume-overload left ventricular dysfunction caused by
valvular insufficiency in 7 patients (VHD group; patients 8
through 14). All patients had been admitted for the treatment of
symptomatic heart failure; New York Heart Association
functional class on admission was II in 2 patients, III in 5, and IV in
7. The study protocol was performed 1 to 2 weeks after initial
management of heart failure. All patients had normal coronary
arteriograms. We studied 7 other patients without clinical evidence of
left ventricular dysfunction (mean age, 58±8 years; 4 men
and 3 women) who had been referred to our hospital for evaluation of
chest pain (control group, Table 1). All control patients had negative
treadmill testing and normal coronary angiograms. Clinical
characteristics of the studied patients and baseline
hemodynamic variables and indexes of left
ventricular function in the studied groups are shown in
Tables 1 and 2, respectively. Left
ventricular ejection fraction of DCM patients was 33±12%
(ranging 16% to 46%, P<.0001 versus controls), whereas
that of VHD patients was 63±7%. It has been well recognized that
ejection phase indexes of left ventricular contraction such
as ejection fraction are often within the normal range in patients with
contractile dysfunction due to valvular
insufficiency.12 13 To obtain an index of left
ventricular systolic function that is more
independent of load and can be clinically estimated with relative ease,
we additionally determined the quotient of end-ejection
arterial pressure and left ventricular
end-systolic volume index (Pee/LVESVI). This
variable is an approximation of left ventricular
end-systolic elasticity,14 15 which has been
experimentally and clinically shown to be relatively independent of
load within a broad range of preload and afterload.16 As
shown in Table 2, the Pee/LVESVI ratio was significantly
smaller in both CHF subgroups (DCM and VHD groups) compared with that
in the control group. Cardiac index was significantly
(P<.05) reduced in VHD patients. One DCM patient (patient
1) had diabetes with a positive glucose tolerance test, and 1 patient
with valvular insufficiency (patient 9) was
hyperlipidemic (total cholesterol >260
mg/dL or 6.72 mmol/L). Two control group patients (patients 1 and
5) had one or two risk factors. In summary, no coronary risk
factor was found in 6 of 7 DCM patients, 6 of 7 VHD patients, and 5 of
7 control patients.
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Study Protocol
The study protocol was approved by the Institutional Review
Committee on Human Research, Faculty of Medicine, Kyushu University.
Written informed consent was obtained from each patient before the
study.
Cardiac catheterization was performed with patients in the fasting state after 5 mg oral diazepam. All cardiovascular medications were discontinued at least 24 hours before the study. Right and left heart catheterization was performed via the femoral approach. Biplane left ventriculograms at the right and left oblique projections were recorded with a 6F pigtail catheter and power injector. At least 20 minutes after the left ventriculography, the following protocols were performed.
First, we examined the effects of the NO synthesis inhibitor L-NMMA (Clinalfa) on the following variables. L-NMMA at doses of 50, 50, and 100 µmol (cumulative doses of 50, 100, and 200 µmol) was administered sequentially. The estimated maximum molar concentration of L-NMMA in our dosing protocol would be 590 µmol/L if resting coronary blood flow of the left coronary artery is assumed to be 170 mL/min. This dose of L-NMMA has been shown to be effective in inhibiting NO synthesis activity in isolated coronary arteries.17 Furthermore, we have demonstrated that this dosing protocol of L-NMMA inhibits acetylcholine (10 µg/min)–induced dilation of large epicardial coronary arteries and increases in coronary blood flow in patients with normal coronary angiograms.18 Systemic arterial pressure, heart rate, 12-lead electrocardiogram, and coronary blood flow velocity at the proximal left anterior descending artery (intracoronary Doppler guide wire) were continuously measured throughout the study. Each dose of L-NMMA was diluted in 5% glucose solution and infused manually over 1 minute into the left coronary artery via a Judkins-type left coronary catheter. At least 2 minutes was allowed to elapse before administration of the next dose of L-NMMA. Coronary angiography was performed at baseline (ie, before L-NMMA administration) and after the final dose of L-NMMA was given to obtain the diameter of the large epicardial coronary artery. Second, papaverine (10 mg) was administered into the left coronary artery to obtain coronary flow reserve under maximal coronary vasodilation.19 Coronary flow reserve was defined as the ratio of maximal coronary blood flow after papaverine to baseline flow.
Quantitative Coronary Angiography and Measurement of
Coronary Blood Flow Velocity
Quantitative coronary angiography was performed with a
Siemens cineangiographic system (Bicor & Hicor), as previously
described.20 21 Nonionic contrast material (iomeprol,
Eisai) was used. An appropriate view was selected that allows clear
visualization of the vessel under study. Throughout the study, the
angle of projection, the distance from the x-ray focus to the
object, and that from the object to the image intensifier were kept
constant. An end-diastolic frame of the coronary
angiogram was selected, and the luminal diameter of the segment of the
artery distal to the Doppler guide wire tip was determined. The tip
of the Judkins catheter with known diameter was used as a reference to
obtain the absolute diameter of the vessel. The accuracy and precision
of our quantitative angiographic system were validated with
precision-drilled models, as previously reported.20
Measurements were made three times, and the averaged value was used for
analysis. Interobserver and intraobserver reproducibilities
were high (r=.96 and r=.98, respectively).
Coronary blood flow velocity was measured with a 0.014-inch Doppler guide wire (FloWire, Cardiometrics Inc) and a fast Fourier transform–based spectral analyzer (FloMap). A Doppler guide wire was advanced via the Judkins catheter, and the tip of the Doppler guide wire was positioned at the proximal portion of the left anterior descending coronary artery. Peak coronary blood flow velocity signal was continuously determined with a spectral analyzer and recorded on a multichannel recorder (Nihon-Koden). Steady-state signals were obtained, and the value based on at least three consecutive beats was used for analysis. Volumetric coronary blood flow was calculated at baseline and after administration of the final dose of L-NMMA using the following formula22 : Coronary Blood Flow (mL/min)=0.5xAveraged Peak Velocity (cm/min)xCross-sectional Area (cm2).
Coronary vascular resistance index was arbitrarily defined as the quotient of mean arterial pressure (millimeters of mercury) and coronary blood flow velocity (centimeter per second) and is presented as a percentage of the baseline value. Changes in diameter and coronary blood flow in response to L-NMMA are expressed as the percent change from the baseline value.
Left ventricular volume and ejection fraction were determined by the area-length analysis of biplane cine ventriculograms. End-systolic volume index was calculated as left ventricular volume at end systole divided by the patient's body surface area.
Statistical Analysis
Data are expressed as mean±SD, unless otherwise indicated.
Comparisons of baseline systemic and coronary
hemodynamic variables within groups were performed
by ANOVA followed by Bonferroni's multiple comparison test if
indicated. Effects of L-NMMA on systemic and coronary
hemodynamics within each group of patients were
analyzed by Student's paired t test. Changes caused
by L-NMMA in coronary diameter and blood flow between the
groups were compared by unpaired t test. A simple linear
regression analysis was used to analyze relations
between changes in coronary blood flow and indexes of left
ventricular function. Differences were considered
statistically significant at a value of P<.05.
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Results |
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Effect of L-NMMA on Systemic Hemodynamics
Baseline heart rate, mean aortic pressure, and pressure-rate product (Systolic Arterial PressurexHeart Rate) did not differ significantly among the three groups (Table 3
). L-NMMA caused a slight but significant
(P<.05) decrease in heart rate in the control group (70±7
to 66±7 beats per minute) but not in the CHF subgroups (Table 3).
L-NMMA increased mean arterial pressure slightly but
significantly in the control group (92±13 to 96±12 mm Hg,
P<.05) but not in the CHF subgroups. Pressure-rate
product was unchanged after L-NMMA in the DCM, VHD, and control
groups.
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Effect of L-NMMA on Epicardial Coronary Diameter
L-NMMA decreased the luminal diameter of the left descending
coronary artery by 6.4%, from 3.14±0.89 to 2.94±0.88 mm
(P<.05) in control patients (Table 3
, Fig 1A). L-NMMA did not significantly change luminal
diameter in either CHF subgroup.
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indicates patients with dilated
cardiomyopathy (DCM); 
, patients with
valvular heart disease (VHD); and 
, control patients.
Data are mean±SEM. ¶P<.05, §P<.01,
P<.0001, baseline vs 200 µmol L-NMMA within each
group; *P<.01, **P<.001 vs both DCM and VHD
groups by ANOVA and Bonferroni's test. None of these variables
differed between the DCM and VHD groups.
Effect of L-NMMA on Coronary Vascular Resistance Index and
Blood Flow
L-NMMA progressively increased coronary vascular
resistance index in a dose-dependent manner in the control group
(P<.0001) as well as the CHF group (P<.05) (Fig 1B). However, constricting responses to L-NMMA were significantly
attenuated in the DCM and VHD groups (both P<.01 versus
control).
L-NMMA decreased coronary blood flow from 53±21 to
35±15 mL/min (P<.001) in control patients. L-NMMA also
decreased coronary blood flow from 56±39 to 50±35 mL/min
(P<.05) in DCM patients and from 57±26 to 51±24 mL/min
(P<.01) in VHD patients. Percent changes in
coronary blood flow induced by L-NMMA were significantly
(P<.0001) smaller in CHF than control patients (DCM,
–8±7%; VHD, –11±6%; control, –34±4%; Fig 1C). There was a
statistically significant correlation between the L-NMMA–induced
changes in coronary blood flow and left ventricular
ejection fraction (P<.01, r=–.620) as well as
between the L-NMMA–induced changes in coronary blood flow and
the Pee/LVESVI ratio (P<.001,
r=–.751) (Fig 2).
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Effect of Papaverine
Coronary flow reserve as assessed by intracoronary
papaverine was not significantly different between the CHF and control
groups (2.8±0.9 versus 3.5±0.4, respectively). There was no
significant relation between the L-NMMA–induced decrease in
coronary blood flow and coronary flow reserve.
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Discussion |
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The basal release of NO in the coronary circulation or its physiological role in regulating coronary blood flow has not been determined in awake patients with heart failure. The novel finding in the present study is that the coronary constricting effect of intracoronary L-NMMA was less in patients with heart failure but was not related to the cause of heart failure. These results support the hypothesis that basal NO production, release, or both are decreased in the coronary circulation of the human failing heart in vivo.
Previous Studies
Recent clinical investigations suggest that basal release of NO is
at least preserved and plays a substantial role in the
peripheral circulation in patients with heart
failure.6 7 8 However, NO synthesis and its contribution to
basal arterial tone may be heterogeneously
affected in different vascular territories in heart
failure.9 10 In the coronary circulation, however,
animal studies have yielded conflicting results. In rats with large
infarction, Drexler et al10 demonstrated that the
vasoconstrictor response to L-NMMA was blunted, suggesting decreased
basal release of NO. In the canine model with heart failure induced by
chronic tachypacing, it also has been reported that the
coronary dilator response to acetylcholine and vasodilation
elicited by cardiac chemoreflex and carotid receptors, all of which are
known to be NO dependent, were impaired after the development of heart
failure.11 23 In contrast, O'Murchu et al9
reported that in large epicardial coronary artery excised from
dogs with pacing-induced heart failure, NO production in
response to 2-adrenergic stimulation was enhanced.
Furthermore, the possibility has been suggested that increased
cytokines, such as tumor necrosis factor-, in heart failure
upregulate an inducible form of NO synthase in the heart and increase
NO production.24 Therefore, we designed the
present study to investigate the role of NO in the regulation of
baseline coronary blood flow in patients with heart
failure.
Basal Release of NO in the Coronary Circulation With
Heart Failure
NO is continuously produced and released by the
endothelium and plays an important role in the
regulation of vasomotion and therefore organ perfusion. We and others
have reported that intracoronary infusion of an
L-arginine analogue such as L-NMMA causes vasoconstriction
of large epicardial and small resistance arteries in
humans.18 25 Our finding that L-NMMA reduced the luminal
diameter of the large epicardial coronary artery and decreased
coronary blood flow in control patients is consistent
with those previous studies and suggests a tonic dilator effect of
basally released NO on the conduit and resistance coronary
arteries.
We demonstrated that the reduction in coronary blood flow in response to L-NMMA was significantly less in patients with heart failure. Since L-NMMA did not change myocardial oxygen consumption, as evidenced by an unaltered pressure-rate product in both groups, our observation indicates that the constricting response of the resistance coronary arteries to L-NMMA is blunted in patients with heart failure. Coronary risk factors such as hypercholesterolemia, diabetes, smoking, and hypertension are known to be associated with endothelial dysfunction1 2 4 26 and reduced bioavailability of NO25 irrespective of heart failure. However, in the present study, only one DCM patient had concomitant diabetes and a current smoking habit, and one VHD patient was hyperlipidemic (total cholesterol >260 mg/dL or 6.72 mmol). Thus, it is unlikely that the difference in clinical characteristics other than heart failure alone determined our results. Intriguingly, the blunted response to L-NMMA was most prominent in patients with more advanced left ventricular dysfunction. This may suggest that basal release of NO from the coronary circulation is relevant to the progression of heart failure.
Although we did not examine the mechanisms by which the constricting response to L-NMMA is attenuated in heart failure, there may be several possibilities. First, the production of NO from the coronary vessels may be decreased. Recent findings that the production of nitrite was decreased in excised coronary arteries from the canine and human failing heart11 27 support this hypothesis. Shear stress exerted on the endothelium is known to facilitate NO release.2 26 28 Pulse frequency (ie, heart rate), pulse pressure, and coronary blood flow velocity were not different in the studied groups. We do not, however, exclude the possibility that reduced shear stress in heart failure might have attenuated basal release of NO. Second, it should be considered whether the attenuated response to L-NMMA observed in the present study was due to the difference in baseline coronary tone. If the basal coronary tone had been already increased in our CHF patients, further constrictor response to L-NMMA could have been smaller than in control patients. We did not examine responses to other vasoconstrictor agents in these patients. However, it has been suggested that vasoconstricting responses are generally augmented but not attenuated in heart failure.29 30 In the present study, we observed comparable vasodilator responses to intracoronary papaverine and baseline vascular resistance, which may suggest that basal coronary tone was comparable in our patients with and without heart failure. Thus, it is unlikely that the attenuated response to L-NMMA was accounted for by the difference in baseline coronary tone. It also has been reported that ouabain, a cardiac glycoside, attenuates acetylcholine-induced endothelium-dependent vasodilation in human subcutaneous arteries in vitro.31 We do not know whether digoxin may account for the attenuated response to L-NMMA in our patients. Digoxin had been taken by nine of the CHF patients but none of the control patients. However, other studies have demonstrated that ouabain does not inhibit acetylcholine-induced relaxation in the coronary artery.32 The latter observation suggests that the effect may be heterogeneous in different vascular beds. Indeed, the response to L-NMMA in our CHF patients with and without digoxin treatment was not significantly different. In any case, our present observation supports the hypothesis that basal release of NO may not be increased in the coronary circulation with heart failure.
Effect of L-NMMA on the Diameter of the Large Epicardial
Coronary Artery
The reduction in the luminal diameter of the large epicardial
coronary artery in response to intracoronary L-NMMA
tended to be greater in the control patients. This decrease in the
coronary diameter must have been at least partly secondary to
the decrease in coronary blood flow by L-NMMA. It is therefore
unknown whether the direct vasoconstricting effect of L-NMMA on the
large epicardial coronary artery is also blunted in heart
failure.
Study Limitations
Study limitations include the following. First, we used 200
µmol L-NMMA cumulatively in the present study. This caused a
slight but significant rise in arterial pressure, and
higher dose of the drug would have caused systemic hypertension. To
avoid secondary changes in coronary blood flow caused by
elevated arterial pressure and hence increased myocardial
oxygen demand, we did not test a higher dose. However, the constrictor
effect of L-NMMA plateaued at doses higher than 50 µmol in CHF
patients (Fig 1B); therefore, it is unlikely that a higher dose of
L-NMMA might have caused larger responses. Second, we did not evaluate
the stimulated release of NO in our patients. Studies from other
laboratories have shown that acetylcholine-induced coronary
vasodilation is impaired in dilated
cardiomyopathy.33 34 Responses to
other endothelium-dependent stimuli such as substance P
remain to be elucidated. Third, it is not known from our study how the
attenuated basal (and stimulated) release of NO may influence the
control of coronary blood flow under
physiologically stressed conditions such as
exercise or tachypacing. Future studies are warranted to address these
questions.
Conclusions
Intracoronary L-NMMA decreased baseline coronary
blood flow in patients with and without heart failure in vivo. The
vasoconstricting effect of L-NMMA was less in CHF patients. Our data
support the hypothesis that basal release of NO in the coronary
circulation is decreased in patients with heart failure caused by
noncoronary artery disease.
Received September 9, 1996; first decision October 11, 1996; accepted December 31, 1996.
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