(Circulation. 2000;101:1899.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Prognostic Impact of Coronary Vasodilator Dysfunction on Adverse Long-Term Outcome of Coronary Heart Disease
From the Department of Internal Medicine IV, Division of Cardiology, J.W. Goethe University, Frankfurt, Germany.
Correspondence to Volker Schächinger, MD, Department of Internal Medicine IV, Division of Cardiology, J.W. Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany. E-mail schaechinger{at}em.uni-frankfurt.de
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Abstract |
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Background—Endothelial vasodilator dysfunction is a characteristic feature of patients at risk for coronary atherosclerosis. Therefore, we prospectively investigated whether coronary endothelial dysfunction predicts disease progression and cardiovascular event rates.
Methods and Results—Coronary vasoreactivity was assessed in 147 patients using the endothelium-dependent dilator acetylcholine, sympathetic activation by cold pressor testing, dilator responses to increased blood flow, and dilation in response to nitroglycerin. Cardiovascular events (cardiovascular death, unstable angina, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary bypass grafting, ischemic stroke, or peripheral artery revascularization) served as outcome variables over a median follow-up period of 7.7 years. Patients suffering from cardiovascular events during follow-up (n=16) had significantly increased vasoconstrictor responses to acetylcholine infusion (P=0.009) and cold pressor testing (P=0.002), as well as significantly blunted vasodilator responses to increased blood flow (P<0.001) and the intracoronary injection of nitroglycerin (P=0.001). Impaired endothelial and endothelium-independent coronary vasoreactivity were associated with a significantly higher incidence of cardiovascular events by Kaplan-Meier analysis. By multivariate analysis, all tests of coronary vasoreactivity were significant, independent predictors of a poor prognosis, even after adjustment for traditional cardiovascular risk factors or the presence of atherosclerosis itself.
Conclusions—Coronary endothelial vasodilator dysfunction predicts long-term atherosclerotic disease progression and cardiovascular event rates. Thus, the assessment of coronary endothelial vasoreactivity can provide pivotal information as both a diagnostic and prognostic tool in patients at risk for coronary heart disease.
Key Words: coronary disease • endothelium • prognosis • acetylcholine • myocardial infarction
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Introduction |
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The endothelium is a complex endocrine and paracrine organ that affects vasoregulation, smooth muscle cell proliferation, platelet aggregation, monocyte and leukocyte adhesion, and thrombosis,1 all of which are cardinal features in the pathogenesis and progression of atherosclerosis.2 Indeed, experimental studies have demonstrated that the functional integrity of the endothelium exerts potent antiatherosclerotic and antithrombotic effects.3 4 5 6
Clinically, endothelial function is most often assessed as a vasodilator response to pharmacological or mechanical stimuli. Numerous studies have shown that the presence of coronary atherosclerotic lesions is associated with impaired endothelium-mediated regulation of vascular tone.7 8 9 10 11 12 More importantly, endothelial vasodilator dysfunction has been observed in patients with traditional coronary risk factors, even in the absence of evidence for atherosclerotic lesions, which suggests that the endothelium is both a target and a mediator of atherosclerosis.13 14 Thus, the hypothesis has been forwarded that endothelial vasodilator function may serve as an index integrating the overall stress imposed by coronary risk factors.15
If such a concept was correct, then coronary endothelial vasodilator dysfunction would not only predict coronary disease progression and cardiovascular event rates, but the assessment of endothelial vasodilator function would emerge as an important diagnostic and prognostic tool in patients with coronary heart disease. Therefore, we prospectively investigated whether coronary endothelial dysfunction predicts disease progression and cardiovascular event rates.
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Methods |
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Patient Population
The patient population was composed of 147 consecutive patients undergoing an assessment of coronary endothelial vasoreactivity; the minimum duration of follow-up was >12 months. A total of 112 patients were studied at the University of Freiburg, Germany, from 1988 to 1994, and 35 patients were studied at the University of Frankfurt, Germany, from 1995 to 1997. The study protocol was approved by the ethics committees of both universities, and informed consent was obtained from each patient. Patients undergoing either routine diagnostic catheterization for the evaluation of chest pain or percutaneous transluminal coronary angioplasty (PTCA) for single-vessel disease were studied. In patients undergoing PTCA, another vessel without significant obstruction was examined (either the left anterior descending or left circumflex artery). Patients with unstable angina, vasospastic angina pectoris, recent myocardial infarction, valvular heart disease, clinical evidence of heart failure, or left ventricular hypertrophy were excluded from the study.
The following risk factors for coronary artery disease were assessed at the time of coronary vasoreactivity testing: hypertension, hypercholesterolemia, smoking, family history, and evidence of atherosclerosis.
Hypertension was defined as a history of hypertension (blood pressure
>140/90 mm Hg) for >2 years that required the initiation of
antihypertensive therapy by the primary physician.
Hypercholesterolemia was defined as fasting
total serum cholesterol values exceeding the
75th percentile when adjusted for age and sex.
Smoking was defined as a history of smoking for >2 pack-years.
However, all smokers refrained from smoking 
4 hours before
examination. A positive family history for coronary artery
disease was defined as evidence of coronary artery disease in a
parent or sibling who was younger than 60 years of age at the time of
diagnosis. Angiographic evidence of atherosclerosis was
defined as luminal irregularities in any vessel. However, luminal
narrowing had to be <30% stenosis in the tested vessel.
Long-Term Follow-Up
Clinical long-term follow-up was performed using a questionnaire
that was sent to patients and primary physicians. All information
regarding potential cardiovascular events was validated
by source data, including the analysis of repeat
coronary angiograms, discharge letters, or charts of hospital
stays.
The following events were assessed during long-term follow-up. Death
from any cause was documented. Cardiovascular death was
defined as death due to a myocardial or cerebral infarction or
documented sudden cardiac death. Unstable angina pectoris was defined
as hospitalization due to unstable angina pectoris of Braunwald
classification IIB or IIIB. Myocardial infarction was defined as an
elevation of creatine kinase levels >2 times the upper limit or new ST
elevations (>0.1 mV) in 2 leads. PTCA counted only when performed in
a newly developed (de novo) stenosis during follow-up.
Coronary artery bypass grafting (CABG) was defined as the
necessity of CABG in 1 de novo lesion during long-term follow-up.
Similarly, peripheral bypass
revascularization was defined as the need for the
surgical revascularization of a de novo
stenosis of the peripheral arteries.
Ischemic stroke was defined as clinical evidence of stroke
without intracranial hemorrhage on brain imaging studies.
Cardiovascular events included the occurrence of cardiovascular death, unstable angina pectoris, myocardial infarction, PTCA, CABG, ischemic stroke, or revascularization of peripheral arteries during long-term follow-up. Cardiovascular events that could be related to the vessel in which vasoreactivity was initially tested were classified as target vessel–related events.
Because angiotensin-converting enzyme (ACE) inhibitors and statins might influence both endothelial vasodilator function and disease progression, chronic therapy with these drugs during long-term follow-up was documented.
Study Design
Vasoactive therapy, including calcium channel blockers,
long-acting nitrates, and ß-blockers, was discontinued 24 hours
before cardiac catheterization. ACE
inhibitors were discontinued 3 days before the study. The
study protocol has been previously described in detail.11
In brief, the endothelium-dependent vasodilator
acetylcholine (10-8 to
10-6 mol/L) was subselectively infused via an
infusion catheter into the vessel under study. Sympathetic activation
by cold pressor testing was performed by immersing the patient’s hand
in ice water for 90 seconds. Flow-dependent dilation was assessed
either 90 seconds after the injection of 7 mg of papaverine or 2
minutes after the infusion of 2.4 mg/min adenosine into the
midportion of the vessel under study to maximally increase blood flow.
Flow-dependent dilation was assessed in a proximal coronary
arterial segment exposed to the increased blood flow but
not to the vasodilator agents papaverine or adenosine.
Nitroglycerin (0.2 to 0.3 mg) was injected into the
ostium of the left main stem to assess maximal
endothelium-independent epicardial vasodilator
capacity.
Quantitative Coronary Angiography
Videodigitized end-diastolic frames were
analyzed by an automatic contour detection technique, as
previously described.11 A 6- to 8-mm proximal
coronary artery was measured to obtain a mean diameter after
the various tests. Acetylcholine and cold pressor test responses were
measured in a predefined segment immediately distal to the tip of the
infusion catheter. In the same segment, flow-dependent dilation could
be assessed after advancing the infusion catheter further distally in
the majority of patients. The accuracy, reproducibility, and inter- and
intraobserver variability of these measurements have been published
previously.16
Statistical Analysis
Data are expressed as mean±SD. Statistical comparisons were
made by Student’s t test if data were normally distributed;
otherwise, they were made by the nonparametric Mann-Whitney
U test. Cumulative event rates were estimated by Kaplan Meier survival
curves for categorical variables. Probability values were
determined by the use of the log-rank statistic. For Kaplan-Meier
analyses, vasoconstriction (<0% luminal area change)
to acetylcholine or cold pressor testing was considered abnormal,
whereas vasodilation (0% luminal area change) was classified as a
normal response. In addition, Cox regression analysis was used
to examine the potential relationships between continuous variables
and events during the follow-up period. Multivariate
analysis using Cox regression techniques was performed to
examine potential interactions among the entered covariates. The
variables included in the models were coronary
vasoreactivity, angiographic evidence of
atherosclerosis, arterial hypertension,
serum cholesterol level, sex, smoking, diabetes mellitus,
age, and a positive family history for coronary artery disease.
Statistical significance was assumed if the null hypothesis could be
rejected at the P=0.05 level. All statistical
analysis was performed using SPSS for Windows 8.0 (SPSS
Inc).
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Results |
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Patient Characteristics
The baseline characteristics of the 147 patients are summarized in Table 1
. The mean duration of follow-up
was 6.7±3.2 years (range, 1.1 to 10.6 years; median, 7.7 years).
During follow-up, a total of 16 patients experienced a
cardiovascular event (Table 2). Nine patients experienced 1 event, 3
patients had 2 events, 3 patients had 3 events, and 1 patient had 4
events during follow-up. In all these patients, only the event that
occurred first was used for the analysis of
cardiovascular events. In addition, 2 patients died of
cancer (37 and 53 months after the vasomotor testing), 1 patient
committed suicide after 50 months, 1 patient died from complications
during right heart catheterization for the
diagnostic work-up of a pericardial effusion of unknown
origin after 113 months, and 1 patient died of nonischemic
complications during hemodialysis after 118 months.
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Clinical Determinants of Prognosis
On univariate analysis by Kaplan-Meier curves
(categorical parameters) or Cox regression analysis
(continuous variables), angiographic evidence of
atherosclerosis (P=0.0009),
arterial hypertension (P=0.008), and serum
cholesterol level (P=0.04) were significantly
associated with the occurrence of cardiovascular
events. Age (P=0.87), sex (P=0.36), and a
positive family history of coronary artery disease
(P=0.87) were not associated with a poor outcome, and a
tendency, albeit one that was not statistically significant, was
observed for diabetes mellitus (P=0.11) and smoking
(P=0.09). Neither lipid-lowering therapy nor
ACE-inhibitor therapy were associated with improved
long-term outcome by Kaplan-Meier analyses. A total of 9 of 58
patients receiving lipid-lowering therapy experienced a
cardiovascular event compared with 7 of 89 patients who
did not receive lipid-lowering therapy (P=0.15 by
2).
Coronary Vasoreactivity and Prognosis
During the initial testing of coronary vasoreactivity, 145
patients received an intracoronary infusion of acetylcholine.
Flow-dependent dilation was analyzed in 119 patients, 81
patients underwent cold pressor testing, and 142 patients received an
intracoronary injection of nitroglycerin.
Infusion of the maximum dose of acetylcholine elicited vasodilation in 50 patients (34%) and vasoconstriction in 95 patients (66%). The mean epicardial luminal area change was -9.9±26%. Sympathetic activation by cold pressor testing was associated with epicardial artery vasodilation in 29 patients (36%), whereas vasoconstriction was observed in 52 patients (64%), with a mean change in epicardial luminal area of -4.2±18%. Increased blood flow resulted in a mean epicardial luminal area change of 15±11%. An injection of nitroglycerin resulted in a mean epicardial luminal area change of 34±20%.
As illustrated in Figure 1, patients
experiencing cardiovascular events during follow-up had
significantly increased vasoconstrictor responses to acetylcholine
infusion and cold pressor testing, as well as significantly blunted
vasodilator responses to increased blood flow and an
intracoronary injection of nitroglycerin.
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Figure 2 shows the cumulative proportion
of patients without cardiovascular events according to
the presence of a vasodilator or vasoconstrictor response to
acetylcholine or cold pressor testing, as well as according to tertiles
of flow-dependent or nitroglycerin-induced epicardial
artery dilation. The incidence of cardiovascular events
was significantly higher in patients exhibiting vasoconstrictor
responses to acetylcholine or cold pressor testing. Likewise, the
incidence of cardiovascular events increased
significantly with decreasing vasodilator responses to increased blood
flow or nitroglycerin.
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Cox regression analysis using the vasomotor responses as continuous variables also demonstrated a significant association with the combined end point of cardiovascular events, with P=0.056 for acetylcholine testing, P=0.002 for cold pressor testing, P=0.0006 for flow-dependent dilation, and P=0.004 for nitroglycerin-induced vasodilator response. In addition, flow-dependent dilation normalized to nitroglycerin-mediated vasodilator capacity still remained a significant predictor (P=0.039) for the occurrence of cardiovascular events during follow-up. Thus, impaired coronary endothelial vasodilation is associated with a significantly higher incidence of cardiovascular events during long-term follow-up.
Multivariate Analysis
To identify coronary endothelial
vasodilator dysfunction as an independent predictor of
cardiovascular events during long-term follow-up,
multivariate analyses were performed; these
included the classic risk factors for coronary artery disease
and angiographic evidence of atherosclerosis. As shown
in Table 3, the independent predictors of
a poor outcome were impaired endothelial
vasoreactivity, angiographically visible coronary
atherosclerosis, and arterial hypertension.
Cholesterol serum levels achieved only borderline
significance after controlling for the presence of angiographically
visible atherosclerosis. Although the significance
levels did vary slightly for the individual tests applied, in part
because of the different number of patients studied, all 3 tests
assessing the various mechanisms of
endothelium-mediated coronary vasoregulation
proved to be independent predictors of cardiovascular
events during long-term follow-up. However, a blunted vasodilator
response to nitroglycerin also remained a significant
independent predictor of a poor long-term outcome, suggesting that
endothelium-dependent and
endothelium-independent vasodilator capacity are
important for atherosclerotic disease progression.
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Target Vessel–Related Events
Finally, because previous studies suggested that coronary
endothelial vasoreactivity may be
heterogeneous, a reanalysis of the data was
performed in which only cardiovascular events related
to the coronary artery in which vasoreactivity testing was
performed were counted. A total of 10 events restricted to the
initially tested target vessel occurred during long-term follow-up
(PTCA, 5 patients; CABG, 6 patients; myocardial infarction, 1 patient;
2 patients had both PTCA and subsequent CABG). As for overall
cardiovascular events, target vessel–related events
during follow-up were associated with a significantly increased
vasoconstrictor response to acetylcholine (P=0.02) and cold
pressor testing (P=0.01), as well as significantly blunted
coronary vasodilator responses to increased blood flow
(P=0.001) and nitroglycerin
(P=0.009) and reduced flow-dependent dilation normalized for
nitroglycerin-induced dilator capacity
(P=0.02). Because a different protocol to induce
flow-dependent dilation was used in 16 patients (adenosine),
the data for the 103 patients receiving papaverine to stimulate
increased blood flow were analyzed separately; they gave
essentially identical results.
Figure 3 illustrates the coronary
angiogram of a patient who developed an acute coronary syndrome
3.7 years after the testing of coronary vasoreactivity. This
patient’s focal coronary atherosclerotic disease progression
during follow-up correlated closely with the profound vasoconstrictor
response to acetylcholine, indicating endothelial
vasodilator dysfunction at the time of the initial study.
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Discussion |
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The results of the present study demonstrate that coronary endothelial vasodilator dysfunction is an independent predictor of atherosclerotic disease progression and cardiovascular event rates. The predictive power of coronary endothelial function on the clinical outcome of coronary artery disease strongly supports the concept that endothelial function serves as an integrating index of overall coronary risk factor stress. Thus, the assessment of coronary endothelial vasoreactivity seems to be an important diagnostic and prognostic tool in coronary artery disease. This is the first study to show the long-term prognostic significance of coronary vasoreactivity, thereby extending very recently published observations that endothelium-mediated coronary blood flow regulation might contribute to ischemic manifestations of coronary artery disease.17
Coronary endothelial vasoreactivity was assessed by different stimuli to elicit endothelium-dependent vasodilation. Acetylcholine, the classic stimulus for endothelium-mediated relaxation, acts via muscarinic membrane receptors with signal transduction through G proteins to mediate the release of the predominantly relaxing factor nitric oxide,18 as well as an endothelium-derived hyperpolarizing factor19 that counteracts the direct vasoconstrictor effects of acetylcholine via muscarinic receptors on the smooth muscle layer. A vasodilator response to acetylcholine indicates preserved endothelial vasodilator function.20 Increased blood flow elicits the strictly endothelium-dependent vasodilator response by activating endothelial nitric oxide synthase through phosphatidylinositol-3-OH kinase/Akt-mediated phosphorylation of the enzyme.21 Sympathetic activation by cold pressor testing integrates the effects of adrenergic receptor stimulation in both the endothelium and the smooth muscle cell layer and flow-dependent epicardial vasodilation secondary to increased coronary blood flow due to augmented myocardial demand.8 16 22 Previous studies have demonstrated that coronary vasomotor responses to the sympathetic activation induced by mental stress or cold pressor testing correlate closely with vasomotor responses to acetylcholine,11 23 suggesting that a coronary vasodilator response to sympathetic activation reflects the functional integrity of the endothelium.16
Endothelial Dysfunction and Prognosis
In the present study, all 3 tests to assess coronary
endothelial vasoreactivity were independent predictors
of cardiovascular event rates, indicating that the
predictive power of endothelial dysfunction is not
limited to a specific mechanism to mediate
endothelium-dependent dilation. Importantly, the
predictive value of coronary endothelial
vasodilator dysfunction was independent of the classic risk factors for
coronary artery disease. Indeed, when the vasomotor responses
of the different tests to assess coronary
endothelial vasoreactivity were entered into the
multivariate analyses, the classic risk factors
were no longer significant, independent predictors of a worse clinical
outcome during follow-up, with the exception of arterial
hypertension. Moreover, coronary endothelial
vasodilator dysfunction remained an independent predictor of disease
progression, even after controlling for angiographic evidence of
coronary atherosclerosis, suggesting that even
once atherosclerosis is present, coronary
endothelial vasodilator dysfunction is important. Thus,
the assessment of coronary endothelial
vasoreactivity may indeed serve as an integrating index of the overall
stress imposed by risk factors on the arterial wall.
Although previous studies showing a close correlation between the presence of well-established risk factors and endothelial dysfunction supported a role for endothelial function to predict an intermediate biological outcome, the results of the present study now firmly establish coronary endothelial vasodilator dysfunction as an independent prognostic parameter for an adverse long-term outcome of coronary heart disease. These data considerably extend previous findings showing that coronary endothelial vasodilator dysfunction might contribute to the acute ischemic manifestations of coronary artery disease.24 25 26 27
Endothelium-Independent Dysfunction and
Prognosis
In addition to endothelial vasodilator
dysfunction, however, the impaired dilator response to exogenous nitric
oxide also seems to be of prognostic significance in patients with
coronary artery disease. Indeed, previous studies showed a
significant inverse relationship between the arterial
dilator response to nitroglycerin and
endothelium-dependent dilation.12 28 29
Taken together, these findings suggest that the abnormality in
vasodilator function in patients at risk for
atherosclerosis is not only confined to
endothelium-dependent mechanisms, but may also comprise
an impairment in smooth muscle dilator function. One might speculate
that the blunted coronary vasodilation in patients with a poor
prognosis might simply reflect the presence of
atherosclerosis, leading to increased stiffness of the
vessel wall. However, these patients exhibited significantly enhanced
constrictor responses to acetylcholine and cold pressor testing,
indicating the presence of preserved vasoreactivity of the smooth
muscle cell layer. Nevertheless, the present study in humans can
obviously not define the mechanisms responsible for the association
between impaired coronary vasodilator function and the
progression of atherosclerosis.
However, it is well documented that atherosclerotic risk factors are associated with the overproduction of oxygen-derived free radicals in the vascular wall.30 31 32 Reactive oxygen species can directly activate a whole array of genes implicated in the pathogenesis and progression of atherosclerosis via nuclear factor kappa B–mediated transcriptional activation,33 and they also avidly scavenge both endogenous and exogenous nitric oxide, thereby decreasing the bioavailability of nitric oxide to the smooth muscle cell.34 Thus, it is tempting to speculate that a blunted dilator response mirrors the oxidative stress imposed on the vascular wall, which in turn will determine atherosclerotic disease progression. Increased oxidative stress might affect the bioactivity of both endogenous and exogenous nitric oxide. However, the fact that flow-dependent vasodilation is of prognostic importance, even after normalization to endothelium-independent, nitroglycerin-induced vasodilation, clearly underscores the role of endothelial dysfunction.
Somewhat surprisingly, lipid-lowering therapy with statins was not an independent predictor of improved outcome in our patient population. This finding might be explained either by the rather small number of patients to detect any beneficial effects of statin therapy on disease progression or by the still-restricted use of statins in the late 1980s and early 1990s, when most patients were initially studied. Lipid-lowering therapy was initiated only in patients who had considerably elevated total cholesterol levels. Currently ongoing multicenter trials will ultimately determine whether an improvement in coronary endothelial function by statin treatment is directly related to the well-established beneficial effects of statins on prognosis in patients with coronary artery disease.35
Limitations
Although the number of patients and, thus, the number of events
seems to be rather small, the present study represents the
largest patient cohort studied to date to assess coronary
endothelial vasodilator function, and it is also the
first to report clinical outcome over a 7.7-year (median) observation
period. Nevertheless, larger trials with larger patient populations
should be performed to confirm our data and, more importantly, to
establish the potential beneficial role of reversing coronary
endothelial dysfunction by interventional strategies
for long-term atherosclerotic disease progression. Moreover, although
all consecutive patients undergoing this highly invasive protocol were
included in the long-term follow-up analysis, long-term
evaluation was not a prespecified end point at the time of
coronary vasoreactivity testing. Finally, enrollment of
patients in the study was based on a successfully performed invasive
assessment of coronary vasoreactivity with
intracoronary instrumentation, which might have introduced a
selection bias. However, clinical follow-up was completed for all
patients initially studied. Thus, despite the limitations mentioned
above, we think that our data demonstrate, for the first time, that
endothelial dysfunction of large epicardial arteries is
important for coronary atherosclerotic disease progression.
In summary, the results of the present study demonstrate that coronary endothelial vasodilator dysfunction predicts long-term atherosclerotic disease progression and cardiovascular event rates. Thus, the assessment of coronary endothelial vasoreactivity can provide pivotal information, both as a diagnostic and prognostic tool in patients at risk for coronary heart disease. Importantly, establishing coronary endothelial vasodilator dysfunction as a prognostic index that integrates the overall stress imposed by coronary risk factors might provide a tool to predict the impact of an intervention on coronary disease progression and cardiovascular event rates, as previously suggested by the beneficial effects of cholesterol-lowering therapy on coronary endothelial vasodilator function.36 37
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Acknowledgments |
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Supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 553). We thank Mrs B. Jung for her expert technical assistance in data collection and analysis of the angiograms.
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Footnotes |
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This article originally appeared online only with the March 28, 2000 issue of Circulation. (Circulation. 2000;101:r1–r8.)
Received February 25, 2000; revision received March 18, 2000; accepted March 18, 2000.
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 R. E. Schmieder, C. Delles, A. Mimran, J. P. Fauvel, and L. M. Ruilope Impact of Telmisartan Versus Ramipril on Renal Endothelial Function in Patients With Hypertension and Type 2 Diabetes Diabetes Care, June 1, 2007; 30(6): 1351 - 1356. [Abstract] [Full Text] [PDF]
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T. J. Anderson Prognostic Significance of Brachial Flow-Mediated Vasodilation Circulation, May 8, 2007; 115(18): 2373 - 2375. [Full Text] [PDF]
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H. Viswambharan, J. M. Carvas, V. Antic, A. Marecic, C. Jud, C. E. Zaugg, X.-F. Ming, J.-P. Montani, U. Albrecht, and Z. Yang Mutation of the Circadian Clock Gene Per2 Alters Vascular Endothelial Function Circulation, April 24, 2007; 115(16): 2188 - 2195. [Abstract] [Full Text] [PDF]
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 R. J. Bisoendial, J. J. P. Kastelein, S. L. M. Peters, J. H. M. Levels, R. Birjmohun, J. I. Rotmans, D. Hartman, J. C. M. Meijers, M. Levi, and E. S. G. Stroes Effects of CRP infusion on endothelial function and coagulation in normocholesterolemic and hypercholesterolemic subjects J. Lipid Res., April 1, 2007; 48(4): 952 - 960. [Abstract] [Full Text] [PDF]
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U. Landmesser, S. Spiekermann, C. Preuss, S. Sorrentino, D. Fischer, C. Manes, M. Mueller, and H. Drexler Angiotensin II Induces Endothelial Xanthine Oxidase Activation: Role for Endothelial Dysfunction in Patients With Coronary Disease Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 943 - 948. [Abstract] [Full Text] [PDF]
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C. Murphy, G. S. Kanaganayagam, B. Jiang, P. J. Chowienczyk, R. Zbinden, M. Saha, S. Rahman, A. M. Shah, M. S. Marber, and M. T. Kearney Vascular Dysfunction and Reduced Circulating Endothelial Progenitor Cells in Young Healthy UK South Asian Men Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 936 - 942. [Abstract] [Full Text] [PDF]
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Y. Hattori, S. Hattori, X. Wang, H. Satoh, N. Nakanishi, and K. Kasai Oral Administration of Tetrahydrobiopterin Slows the Progression of Atherosclerosis in Apolipoprotein E-Knockout Mice Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 865 - 870. [Abstract] [Full Text] [PDF]
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Z. Yang, K. Venardos, E. Jones, B. J. Morris, J. Chin-Dusting, and D. M. Kaye Identification of a Novel Polymorphism in the 3'UTR of the L-Arginine Transporter Gene SLC7A1: Contribution to Hypertension and Endothelial Dysfunction Circulation, March 13, 2007; 115(10): 1269 - 1274. [Abstract] [Full Text] [PDF]
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 A. K. Nightingale, J. G. Crilley, N. C. Pegge, E. A. Boehm, C. Mumford, D. J. Taylor, P. Styles, K. Clarke, and M. P. Frenneaux Chronic oral ascorbic acid therapy worsens skeletal muscle metabolism in patients with chronic heart failure Eur J Heart Fail, March 1, 2007; 9(3): 287 - 291. [Abstract] [Full Text] [PDF]
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J. T. Kuvin, A. Mammen, P. Mooney, A. A. Alsheikh-Ali, and R. H. Karas Assessment of peripheral vascular endothelial function in the ambulatory setting Vascular Medicine, February 1, 2007; 12(1): 13 - 16. [Abstract] [PDF]
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