Author + information
- Received August 28, 2009
- Accepted September 23, 2009
- Published online November 1, 2009.
- Christian Heiss, MD⁎,
- Jan Balzer, MD⁎,
- Till Hauffe, BS†,
- Sandra Hamada, MD‡,
- Emilia Stegemann, MD†,
- Thomas Koeppel, MD‡,
- Marc W. Merx, MD⁎,
- Tienush Rassaf, MD⁎,
- Malte Kelm, MD⁎ and
- Thomas Lauer, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Thomas Lauer, Medizinische Klinik B, Heinrich-Heine University, Moorenstrasse 5, 40225 Düsseldorf, Germany
Objectives The aim of this study was to investigate the effect of diagnostic transradial catheterization on vascular function of upstream brachial artery (BA).
Background The transradial access has recently become an alternative to transfemoral cardiac catheterization. A potential caveat of this approach lies in possible sustained physical radial artery (RA) damage.
Methods We studied 30 patients (age 61 ± 11 years) undergoing diagnostic coronary angiography with the transradial access (5-F). Endothelium-dependent, flow-mediated vasodilation (FMD) was measured before and at 6 and 24 h after catheterization of the right-sided RA and BA with high-resolution ultrasound. The left-sided RA served as a control.
Results Transradial catheterization significantly decreased FMD in the RA (overall mean 8.5 ± 1.7% to 4.3 ± 1.6%) and the upstream BA (overall mean 4.4 ± 1.6% to 2.9 ± 1.6%) at 6 h. Subgroup analysis showed that FMD of both arteries at 6 h was significantly lower in active smokers and that it only remained impaired at 24 h in this group, whereas nonsmoker FMD fully recovered. The degree of BA but not RA FMD dysfunction was related to the number of catheters used, with no change after 2 catheters, 1.9 ± 1.2% decrease (6 h) and recovery (24 h) after 3 catheters, and 3.9 ± 1.2% decrease (6 h) without recovery (24 h) after 4 to 5 catheters. The RA dysfunction correlated with the baseline diameter. The contralateral control RA exhibited no change ruling out systemic effects.
Conclusions Transradial catheterization not only leads to dysfunction of the RA but also the upstream BA, which is more severe and sustained in smokers and with increasing numbers of catheters.
Flow-mediated vasodilation (FMD) of the brachial artery (BA) represents the most widely accepted noninvasive standard method for the assessment of endothelial dysfunction, which is suggested to play a significant role in the development and progression of atherosclerosis (1–3). The FMD measurement has gained growing interest as several studies indicated that a decreased FMD response predicts arterial disease progression with intimal thickening and increased cardiovascular mortality (4,5). Several cardiovascular risk factors have been shown to lead to acute and chronic FMD impairment (2,6). Physical damage to the vascular endothelium might also be a cause of functional impairment and might lead to arterial disease (7). In the context of BA FMD, this is particularly important, because the transradial route to perform coronary angiograms and percutaneous coronary interventions is an emerging safe alternative to the femoral access due to its lower bleeding complications (8–10). In animal and human studies, oversized sheaths have been demonstrated to chronically impair endothelial and smooth muscle cell function, leading to intimal thickening and luminal loss potentially impacting the quality of the radial artery (RA) as a bypass graft for coronary artery bypass grafting surgery in patients with coronary artery disease (CAD) (11–13). However, whether catheterization might also affect other vessels also being in contact with the catheter, including the BA, and which factors determine the functional recovery are unclear.
In this study, we hypothesize that routine cardiac diagnostic catheterization causes a vascular dysfunction not only to the radial but also to the BA. In a proof-of-concept study, we noninvasively studied the effect of transradial diagnostic cardiac catheterization on endothelium-dependent and endothelium-independent vasodilation of the BA and RA in patients.
We measured endothelium-dependent FMD and nitroglycerin-mediated endothelium-independent vasodilator function in the RA and BA before as well as 6 and 24 h after right-sided transradial cardiac catheterization (sheath removal) in patients undergoing diagnostic coronary angiography. The contralateral left RA served as a control.
We included 30 consecutive patients undergoing diagnostic coronary angiography with suspected CAD. Patients were excluded from the study if they had undergone previous radial cannulation or had an abnormal Allen test result consistent with insufficient ulnar collateral supply. Other exclusion criteria were acute inflammation (C-reactive protein >0.5 mg/dl), malignancies, heart rhythm other than sinus rhythm, and heart failure New York Heart Association functional class III to IV. All patients provided informed consent, and the study protocol was approved by the local ethics board.
Transradial cardiac catheterization
The right RA was cannulated with a 5-F (external diameter 2.29 mm), 7-cm-long sheath (Cordis, Johnson & Johnson, Piscataway, New Jersey). After sheath insertion, all patients received 0.2 mg nitroglycerin intra-arterially to prevent vasospasm and 5,000-IU heparin intravenously to prevent thrombosis. The angiography was performed with a monoplane X-ray system. Primarily, a Judkins left 3.5 catheter was used for the left coronary artery, and a Multipurpose catheter was used for the right coronary artery and the left ventricular angiogram. If necessary, further catheters included Judkins left 4 and 5, Amplatz left 1, and Judkins right 4 and 5. At the end of the procedure, the sheath was removed immediately, and a wrist clamp (Terumo, Eschborn, Germany) was applied for 4 h (13 ml).
Determination of vascular function with ultrasound
Images were acquired with high-resolution ultrasound (Vivid I, GE Healthcare, Milwaukie, Wisconsin) with a 15-MHz linear probe consistent with the current guidelines (3) and as previously described (6,14,15). Briefly, baseline studies were performed from 7:00 am to 8:00 am in an air-conditioned room with constant temperature. At each time point, the left (noncannulated) and right (cannulated) RA functions as well as right BA vasodilator functions were assessed with FMD and glycerol trinitrate (GTN).
Measurement of FMD
RA function was determined at a landmark 2 to 3 cm proximal the sheath insertion point. Baseline heart rate and blood pressure were recorded. Baseline measurements included RA diameter and RA flow velocity. Subsequently, a blood pressure cuff was inflated at the forearm to suprasystolic pressures for 5 min. Upon cuff release, the RA flow measurements were repeated to demonstrate hyperemia. The RA diameter was measured 60 to 90 s after cuff deflation. The opposite arm and the right BA were measured in the same fashion. The sequence was in random order.
Determination of GTN
Sublingual nitroglycerin (0.4 mg) was administered. Repeat flow and diameter measurements were recorded for both arms at 4 min to assess endothelium-independent vasodilation.
Image Analysis, Calculation of Vasodilation, and Wall Shear Stress (WSS)
The image and flow analyses were performed offline from recorded loops with an automated system (Brachial Analyzer 5, Medical Imaging Applications, Coralville, Iowa). All diameter readings were taken at diastole, and flow velocity represents the mean angle-corrected Doppler flow velocity. Vasodilation results are presented as percent change: (Diameterpostischemia − Diameter baseline/Diameterbaseline) × 100. Flow was calculated as π × (Diameter/2)2 × flow velocity (V). Hyperemic blood flow after occlusion of the forearm increases WSS in the RA and BA, which leads to FMD. The WSS was calculated at peak flow (onset of reactive hyperemia) as: 8 × μ × V/Diameter, where blood viscosity (μ) was assumed to be constant at 0.035 dyne × s/cm2. Images were assessed by 1 experienced investigator blinded to the study regime.
Results are expressed as mean ± SD. The primary test for overall time-dependent effects was a 1-way repeated measurement analysis of variance (ANOVA). To test for the effects of smoking status and number of catheters, a 2-way repeated measurements ANOVA was performed, with time being the intra-subject factor and smoking status or number of catheters being between-subject factors. The ANOVA and unadjusted Holm-Sidak post hoc tests were computed with SigmaStat 3.5 (Systat Software, Inc., San Jose, California).
The characteristics of the study population are summarized in Table 1. There was no difference in mean arterial pressure and heart rate between the study time points (Table 2), excluding sympathetic activation of study subjects. The mean catheterization time was 16 ± 16 min, and the necessary mean volume of contrast agent was 97 ± 49 ml. The number of catheters used varied between 2 and 5 (16 × 2, 10 × 3, 3 × 4, 1 × 5 catheters). No vascular complications including bleeding or vasospasm occurred in the patients.
Endothelial dysfunction in BA and RA after transradial cardiac catheterization
The experimental set-up and overall results are depicted in Figure 1 (solid bars: right RA, hatched bars: right BA, open bars: left RA; 1-way ANOVA). Baseline FMD was 4.4 ± 1.6% in the right BA, 8.5 ± 1.7% in the right RA, and 8.9 ± 2.2% in the left RA (p = 0.56 between RAs) and comparable to previous studies performed in CAD patients with already impaired vasodilator function at baseline (6). Whereas FMD did not change in the control (left RA), FMD was significantly decreased in the right intervention arm at 6 h (BA: 2.9 ± 1.5%; RA: 4.3 ± 1.6%). At 24 h, RA FMD recovered significantly but was still impaired as compared with baseline values (RA: 6.8 ± 2.0%, p < 0.001 vs. 6 h and baseline). Overall, BA FMD remained impaired at 24 h (3.3 ± 1.6%, p = 0.003 vs. baseline, p = 0.247 vs. 6 h).
The baseline diameter of the BA and RA was unchanged at 6 h (Table 2). At 24 h, the baseline diameter of the BA (4.41 ± 0.81 mm) and RA (2.75 ± 0.48 mm) but not the left-sided control RA was significantly increased (BA: 4.61 ± 0.81 mm, p = 0.026 vs. baseline; RA: 2.88 ± 0.42 mm, p = 0.004 vs. baseline). Because WSS during reactive hyperemia is an important determinant of FMD, depending on the diameter and flow velocity (16,17), we calculated the local instantaneous WSS. The local WSS induced at the onset of reactive hyperemia was not altered by the intervention (baseline: 73 ± 20 dyne/cm2 [right RA], 82 ± 21 dyne/cm2 [left RA], 64 ± 23 dyne/cm2 [right BA]). This suggests that the stimulus for FMD in the BA and RA that depends on the ischemic vasodilator response of the downstream microvasculature is unaltered by the intervention (16,17). This supports the notion that the catheterization indeed causes conduit artery dysfunction, and the results cannot be explained by downstream phenomena, including embolization and/or inflammatory alterations of the microcirculation.
To determine the contribution of endothelium-dependent vasomotor dysfunction to the impairment of FMD after catheterization, we measured the endothelium-independent smooth muscle response to oral GTN after FMD. Our results show that the GTN response significantly decreased in both BA and RA at 6 h (RA: 12.7 ± 2.4% [baseline] vs. 7.5 ± 2.0% [6 h], p < 0.001; BA: 13.1 ± 4.2% [baseline] vs. 8.7 ± 3.5% [6 h], p = 0.001 vs. baseline). The decrease in GTN mediated endothelium-independent vasodilation (BA: −3.5 ± 5.2%, RA: −5.3 ± 3.0%) was not dependent on the number of catheters used. At 24 h, the GTN response recovered partially in the RA (10.0 ± 2.3%, p < 0.001 vs. baseline and 6 h) but remained impaired in the BA (9.5 ± 3.7%, p = 0.005 vs. baseline, p = 0.441 vs. 6 h).
We calculated the ratio of FMD and GTN response to determine the relative contribution of endothelium-dependent to total GTN-mediated vasodilation. This showed a significant decrease from 0.73 ± 0.14 (baseline) to 0.58 ± 0.16 (6 h) and recovery to 0.73 ± 0.16 (24 h) in the right RA, suggesting temporary endothelium-dependent vasodilator dysfunction and that the still-decreased FMD response at 24 h is primarily due to reduced smooth muscle responsiveness. In contrast, FMD/GTN ratio in the BA only tended to decrease at 6 h but did not reach statistical significance during the whole study period. Both GTN response and FMD/GTN ratio were unaffected by the intervention in the control arm. No correlations were observed between the degree of vascular functional impairment and the duration of interventions or volume of contrast media.
BA dysfunction is related to number of catheter changes, and RA dysfunction is related to baseline diameter
The BA FMD decreased progressively with increasing mechanical manipulation, depending on the number of catheter changes (Fig. 2) (2-way ANOVA, p = 0.001). Although BA FMD did not significantly change at 6 h after 2 catheters (Delta FMD −0.1 ± 0.8%), it was progressively decreased after 3 (−1.9 ± 1.2%, p = 0.003 vs. baseline) and 4 to 5 catheters (−3.9 ± 1.0%, p = 0.005 vs. baseline). At 24 h, BA FMD after 3 catheters recovered to baseline values, whereas BA FMD after 4 to 5 catheters remained significantly impaired. In contrast, the RA FMD decreased independent of the number of catheters used (−4.3 ± 1.5%, p = 0.845), potentially due to relative protection by the arterial sheath from further injuries induced by catheter changes. As opposed to the degree of BA dysfunction, the degree of RA dysfunction at 6 h inversely correlated with the baseline diameter, suggesting that sheath insertion leads to a greater dysfunction in smaller-sized vessels (r = 0.49, p = 0.018).
Recovery of function is impaired in active smokers
Because our previous studies have suggested that cigarette smoke exposure might have an impact on vascular regenerative processes (18), we performed a subgroup analysis comparing the FMD responses in active smokers and nonsmokers (Figs. 2C and 2D). There was no significant difference in baseline FMD values between the groups. In active smokers, 6- and 24-h FMD values were significantly lowered in both BA and RA as compared with baseline and respective time-points in nonsmokers. In nonsmokers, 24-h BA and RA FMD was not significantly different from baseline values, suggesting completed functional recovery in this group.
The key findings of the present report are that BA function is impaired along with RA function after transradial cardiac catheterization with a 5-F sheath. Moreover, the degree of BA impairment and recovery was determined by the number of catheters used and current smoking status, whereas the RA dysfunction was related to the RA baseline diameter.
Brachial vasodilator dysfunction after transradial catheterization
No study so far has tested the vasodilator function of the BA after being navigated with the catheter en route to the coronary arteries. We show here for the first time that BA function is impaired after transradial catheterization. Importantly, the degree of BA dysfunction depended on the magnitude of mechanical manipulation as indicated by the number of catheters used. Although BA FMD did not significantly decrease when 2 catheters were used, 3 catheters caused severe yet reversible impairment of BA function, and 4 to 5 catheters caused even more severe and sustained impairment of BA function throughout the observation period of 24 h. These results are in line with classical experimental results showing that small lesions can be covered by spreading and migration of surrounding endothelial cells, whereas larger areas require endothelial proliferation (11). Our present results might have clinical consequences for these patients. First, measuring FMD as a surrogate end point in the catheterized arm might yield false results. Second, mechanical injury has been shown to lead to adverse remodeling. In animal models of arteriosclerosis, denudation of arteries leads to plaque development. In patients, repeated transradial catheterization was shown to lead to intimal thickening and luminal loss of the RA (13). Catheter-related mechanical injury might promote arteriosclerosis even in vessels that otherwise are relatively spared from this disease. Clinical implications are that the number of catheter changes should be minimized to avoid unnecessary injury to the vessel walls.
Smoking leads to slower recovery
We and others have previously shown that cigarette smoke exposure leads to acute impairment of endothelial function and might also have a longer-lasting negative impact on vascular repair mechanisms, including the migratory function of endothelial cells and endothelial progenitor cells (18,19). In the context of the present study, we showed that in active smokers the impairment of endothelial function caused by mechanical irritation and likely physical injury to the endothelium is more severe and the recovery is slower as compared with nonsmokers. Impaired migration of endothelial cells and endothelial progenitor cells in the process of covering the denuded areas might contribute to slower repair. Furthermore, it is likely that a similarly impaired recovery occurs in other areas that are in contact with the catheter, including the coronary orifices. This underscores the necessity to enforce strict smoking cessation and even prevent secondhand smoke exposure in patients undergoing catheterization.
Sheath size determines recovery after radial injury
In the current published reports there are conflicting data regarding the vascular injury inflicted upon the RA by insertion of a sheath during cardiac catheterization. This is important, because this might affect the quality of the RA as a potential bypass graft for coronary artery bypass grafting surgery. It was shown that FMD of the RA is virtually abolished at least for 6 to 10 months after catheterization when 6-F sheaths are used (12,20). One study showed that insertion of a 4-F sheath does not cause a decrease in FMD at 24 h, suggesting that the greater the size of the sheath the greater the inflicted injury to the RA (20). In the present study, a 5-F sheath was used, which is in range of physiologic RA diameter. We observed an inverse correlation between the degree of functional RA impairment and baseline diameter, supporting the notion that vasodilator function of the RA can recover within 24 h (in nonsmokers) and that relatively small-sized sheaths should be used to ensure minimal injury and fast recovery of the RA.
Determinants of vascular dysfunction
Mechanistically, our results suggest that the vascular dysfunction caused by transradial catheterization is not an isolated injury to the endothelium but also to the smooth muscle compartment with impaired responsiveness toward the vasodilator nitroglycerin. Endothelial dysfunction as indicated by decreased FMD might be explained in part by the lower responsiveness of the smooth muscle compartment. This dysfunction is most likely caused by the mechanical irritation of the vascular wall during the sheath insertion and removal, because there was no change in vascular vasodilator function in the contralateral arm. An alternative explanation might be an impaired responsiveness due to high local concentrations of nitroglycerin, which is given as a single bolus injection immediately after sheath placement to prevent vasospasm and would not necessarily affect the left-sided arteries. This possibility and the possible influence of sympathetic activation are ruled out because heart rate and blood pressure did not change, 6-h baseline diameters of right-sided arteries were not significantly greater than at baseline, there was no significant impairment of BA FMD when only 2 catheters were use, and as discussed in the preceding text, left-sided measurements remained unaffected.
Collectively, our results suggest that transradial catheterization leads to dysfunction not only of the RA but also the upstream BA. Clinical implications are that the number of catheters used should be kept to a minimum, strict smoking cessation should be enforced, and sheath size should be matched to the radial arterial diameter to protect vascular function and prevent potential arterial degeneration in the future. Furthermore, FMD measurements as a surrogate of cardiovascular health need to be interpreted with caution after transradial catheterization.
The authors thank Dr. Yerem Yeghiazarians for helpful discussions.
This work was supported by grants from the Deutsche Forschungsgemeinschaft (RA 969/4-1 to Dr. Rassaf; KE 405/5-1 to Dr. Kelm; and GRK 1089, TP 3 to Drs. Rassaf and Kelm), Klinische Forscherkomission to Dr. Lauer, Hans und Gertie Fischer Stiftung to Dr. Lauer, and American Heart Association to Dr. Heiss. Drs. Heiss and Balzer contributed equally.
- Abbreviations and Acronyms
- analysis of variance
- brachial artery
- coronary artery disease
- flow-mediated vasodilation
- glycerol trinitrate
- radial artery
- wall shear stress
- Received August 28, 2009.
- Accepted September 23, 2009.
- American College of Cardiology Foundation
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