Abstract
Background Impairment of endothelial function is an independent predictor of coronary events. The aim of this study was to clarify the influence of arterial access and coronary angiography on endothelial function.
Methods Eighteen patients with stable angina pectoris who underwent coronary angiography were included in this study. Brachial artery flow-mediated dilatation of patients was measured before angiography, after femoral arterial sheath insertion, and after coronary angiography.
Results Of 18 patients, 11 had angiographically apparent atherosclerosis. Flow-mediated dilatation after femoral arterial sheath insertion (mean ± SD, 6.62% ± 3.87%) was found to be significantly lower than either before (10.62% ± 5.18%) or after coronary angiography (11.66% ± 5.30%; P = 0.007 and P = 0.001, respectively). Basal and postangiographic flow-mediated dilatation values were similar. Flow-mediated dilatation significantly decreased after sheath insertion in the group with angiographically normal coronary arteries (14.47% ± 4.34% vs 5.98 ± 4.00%, respectively; P = 0.006), whereas the difference was not significant in patients with CAD (8.17% ± 4.16% vs 7.03% ± 3.92%, respectively).
Conclusions Coronary angiography did not result in endothelial vasomotor dysfunction. Femoral arterial sheath insertion during coronary angiography was associated with a short-lived endothelial dysfunction. Larger studies are needed to interpret the effect of coronary atherosclerosis on attenuation of endothelial response against arterial wall injury.
Impairment of endothelial function is an independent predictor of coronary events.1Endothelial dysfunction occurs in the presence of atherosclerosis or its risk factors and contributes to both initiation and progression of atherosclerotic lesion.2,3It is known that biochemical or mechanical trauma causes endothelial dysfunction.
Some studies have documented development of endothelial dysfunction after percutaneous coronary interventions (PCI).4,5Moreover, recent studies revealed that endothelial dysfunction after PCI is a predictor of in-stent restenosis.6-8Mechanical trauma seems to be a reasonable explanation for endothelial dysfunction after PCI. Similarly, arterial access during coronary angiography leads mechanical trauma to arterial endothelium. This trauma is expected to affect endothelial function, but the impact of femoral arterial access on brachial artery flow-mediated dilatation (FMD) has not been investigated.
Influence of coronary angiography on endothelial function has not been sufficiently studied. There is one study in which a subgroup of 11 patients who underwent coronary angiography was evaluated and no significant effect on endothelial function was observed.4Coronary angiography is an invasive procedure because of arterial sheath insertion and catheter manipulations. Impact of either sheath insertion or coronary catheterization needs to be investigated to clarify endothelial effects of coronary angiography.
This study was designed to assess endothelium-dependent flow-mediated vasodilatation after coronary angiography and to determine if femoral arterial access or coronary catheterization had a specific role on this response.
MATERIALS AND METHODS
Eighteen consecutive patients scheduled for coronary angiography with clinically suspected coronary artery disease were included in this study. Exclusion criteria were acute coronary syndrome or revascularization within the previous month, kidney failure, use of nitrates or nitrate donors in procedure day, or atrial fibrillation. Patients who underwent ad hoc PCI were also excluded from the study. Institutional local ethics committee approved the study protocol, and written informed consent was obtained from all patients.
All patients were fasting and did not receive any anxiolytic agent before coronary angiography. Other drugs were not restricted before coronary angiography. Flow-mediated dilatation measurements were done in angiography room in morning hours to ensure standardization.
Flow-mediated dilatation of the brachial artery was noninvasively examined by 2-dimensional high-resolution ultrasound machine (GE Medical Systems Vivid 7 Pro, GE Vingmed AS, Horten, Norway) with a 12-MHz linear array transducer as described previously and stated in the report of the International Brachial Artery Reactivity Task Force.9A sphygmomanometric cuff was first placed above the antecubital fossa. After baseline longitudinal image of brachial artery is acquired, cuff is inflated to at least 50 mmHg above systolic pressure to occlude brachial artery for 5 minutes. Brachial artery diameter was measured 1 minute after cuff deflation. Brachial artery diameter percent change was calculated and recorded as the FMD of the patient. The variability of the diameter measurement was minimized by calculating the average derived from 3 diameter measurements determined along the longitudinal segment of brachial artery. All measurements were done by the same physician.
Coronary angiography was performed using standard technique and views with Philips Allura Integris II Biplane Angiography machine. Coronary angiography was performed with 6F Judkins catheters. Iomeprol, 400 mg/mL, was used in every patient. Coronary artery disease (CAD) was defined as 20% or greater luminal stenosis of at least one vessel. Angiography duration and amount of contrast material were recorded as well.
Each patient underwent the following protocol: before angiography, patient was prepared properly, baseline FMD was measured before the procedure. After insertion of 6 French (6F) introducer sheath into right common femoral artery, FMD was measured again. Postprocedural FMD and endothelium-independent nitrate-mediated dilatation (NMD) of brachial artery were measured before removal of femoral arterial introducer sheath. Nitrate-mediated dilatation was measured to determine the maximum obtainable vasodilator response. Endothelium-dependent vasodilatation did not exceed nitrate-mediated vasodilatation in any patients. All FMD measurements were done on left brachial artery. The left brachial artery was preferred for convenience of the operator and maintenance of sterile environment.
STATISTICS
Data are expressed as mean ± SD for continuous variables and number and percent for categorical variables. A 2-sided P ≤ 0.05 was considered statistically significant. The Kolmogorov-Smirnov test was used as test of normality. Paired sample t test and independent samples t test were used for normally distributed variables, and the Wilcoxon signed rank test was used for the variables that were not normally distributed. Pearson correlation coefficient was used for analysis of intraobserver variability of brachial FMD. The SPSS statistical software (SPSS 17.0 for Windows Inc, Chicago, IL) was used for all statistical calculations.
RESULTS
The study group consisted of 18 patients (6 men and 12 women), with mean ± SD age of 55.50 ± 5.66 years. Seven of 18 patients had angiographically normal coronary arteries. Baseline characteristics of patients are summarized in Table 1. All patients were under prescription of aspirin. Seven patients were under treatment of angiotensin converting enzyme inhibitors, 7 patients were taking angiotensin receptor blockers, 7 patients were taking β-blockers, 4 patients were taking thiazide diuretics, and 4 patients were taking calcium channel blockers. All hyperlipidemic patients were prescribed statin. Use of these drugs were not associated with FMD.
Correlation coefficient for intraobserver variability of brachial artery diameter measurements was 0.99 (P < 0.001). Measurements before and after femoral access and after coronary angiography are summarized in Table 2. Baseline brachial artery diameters were similar in all measurements. Baseline and postangiographic FMD values were similar (10.62% ± 5.18% vs 11.66% ± 5.30%, respectively). However, FMD measurements after arterial sheath insertion were significantly lower than either before or after coronary angiography (P = 0.009 and P < 0.001, respectively).
Basal FMD was not associated with the sex of the patients. Blood pressure of patients was not correlated with FMD. There was a negative correlation between the number of risk factors and basal FMD (r = −0.77, P < 0.001). Baseline FMD was significantly higher in the patients with angiographically normal coronary arteries (14.47% ± 4.34% vs 8.17% ± 4.16%, P = 0.007), although brachial artery diameters were similar among the patients with angiographically normal coronary arteries and the patients with CAD (3.75 ± 0.32 mm vs 3.89 ± 0.29 mm, P = 0.36). Flow-mediated dilatation significantly decreased after sheath insertion in the group with angiographically normal coronary arteries, whereas the difference was not significant in the patients with CAD. Moreover, decrease in FMD after sheath insertion was more significant in the group with angiographically normal coronary arteries than the group with CAD (8.49% ± 5.22% vs 1.13% ± 4.14%, respectively; P = 0.008). Flow-mediated dilatation was ameliorated in both groups after coronary angiography.
The amount of contrast media used in the angiography of the patients with CAD was higher than that used in the patients with angiographically normal coronary arteries (108.18 ± 36.28 mL vs 54.29 ± 20.50 mL, respectively; P = 0.003). Although the tendency was not significant (818.18 ± 646.60s vs 333.57 ± 160.78 seconds, P = 0.07), the angiography procedure lasted longer in the group with CAD.
DISCUSSION
This is the first study demonstrating that femoral arterial sheath insertion is associated with reversible systemic endothelial dysfunction, which recovers at the end of angiography.
Effects of percutaneous coronary intervention on endothelial function have been investigated well, but effects of coronary angiography alone has not been investigated thoroughly. Recent studies revealed that PCI causes deterioration of endothelial function in either coronary or peripheral arterial vessels.4,5It has been suggested that arterial endothelial injury was responsible for this endothelial response. Documentation of C-reactive protein rise not only after PCI but also after coronary angiography in a recent study suggests that coronary angiography is a traumatic process as well.10Sbarbati et al.11noted significant increase of circulating endothelial cells in both arterial and venous blood samples after coronary angiography with 8F sheaths and catheters. However, Boos et al.12did not observe significant rise in circulating endothelial cells after coronary angiography with 5F and 6F sheath and catheters. Larger sheaths may have contributed to increased endothelial cell detachment and subsequently higher circulating endothelial cell count. Moreover, significant rise in circulating endothelial cells, von Willebrand factor, and soluble E-selectin after PCI in the study of Boos et al. suggests that PCI leads more severe endothelial damage than coronary angiography alone. Increase in circulating endothelial cells, von Willebrand factor, and soluble E-selectin may play a role in systemic endothelial response after local arterial injury.
Warnholtz et al.4demonstrated that tirofiban use attenuated endothelial dysfunction after PCI. They also reported that after coronary angiography of 11 patients with atherosclerotic coronary artery disease, brachial artery FMD had not changed. Our findings are concordant with this study. Moreover, our findings revealed that invariance of FMD after coronary angiography does not mean absence of negative impact on endothelium. Short-lasting endothelial dysfunction may be due to the low intensity of endothelial injury.
Coronary catheterization and radiocontrast agent injection did not result in endothelial dysfunction. Indeed, in both groups, recovery in FMD was observed after angiography compared with FMD after sheath insertion. Radiocontrast agents cause vasodilatation after intra-arterial and intravenous administration and might be responsible for postangiographic improvement of FMD.13,14Although it is not significantly different from baseline, the FMD values of patients with CAD are higher after coronary angiography. This finding brings concerns about whether FMD recovery was spontaneous.
Depressed FMD is a sensitive predictor of coronary atherosclerosis.15,16In this study, it is found that the patients with more cardiovascular risks and those with angiographically visible CAD had endothelial dysfunction, concordant with previous studies.1,17Sheath insertion was associated with endothelial dysfunction in the patients who were angiographically healthy but not in the patients with CAD patients. This might be due to already existing endothelial dysfunction in the CAD group.
Preoperative stress or pain despite local anesthesia during femoral access might have influence on endothelial dysfunction via sympathetic activation. Sympathetic tonus is a determinant of variations in FMD.18Mental stress is known to attenuate brachial FMD.19Patients were told about the result of CAG before the last FMD measurement. Feeling secure from further invasive procedures and relief of stress might contribute to recovery of FMD. However, Ghiadoni et al.20noted that after mental stress, FMD decreased at 30 and 90 minutes and returned toward baseline levels by 240 minutes. Endothelial effect of mental stress is not abruptly eliminated, and it is reasonable to expect persistence of this effect up to the end of coronary angiography.
LIMITATIONS
Small study population was a handicap in analyzing confounding factors with effects of CAD in endothelial response to coronary angiography. Measurements of each patient were recorded on the same screen in chronological order, which did not allow blinding. As there are many other factors, such as use of different drugs, which affect endothelial function, studies with larger population are needed to clarify this issue. We did not measure sympathetic tonus or mental stress in our study.
CONCLUSIONS
Femoral arterial sheath insertion triggers short-lasting systemic endothelial dysfunction. Presence of angiographically proven atherosclerosis might have a negative influence on intensity of endothelial response against arterial wall injury. Further research is needed to establish the mechanism of improvement in FMD whether it is an effect of radiocontrast agent or a spontaneous recovery.