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Wall shear stress in the stented superficial femoral artery in peripheral arterial disease
Atherosclerosis 233 (2014) 76e82
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Wall shear stress in the stented superficial femoral artery in peripheral arterial disease Oliver Schlager a, Sonja Zehetmayer b, Daniela Seidinger a, Bernd van der Loo a, Renate Koppensteiner a, * a b
Department of Medicine II, Division of Angiology, Medical University of Vienna, Vienna, Austria Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 July 2013 Received in revised form 14 November 2013 Accepted 13 December 2013 Available online 4 January 2014
Objective: Local changes in wall shear stress (WSS) contribute to vascular wall thickening and subsequent stenosis. Restenosis after stenting is a major concern, especially in the superficial femoral artery (SFA) of patients with peripheral arterial disease (PAD). Local alterations in WSS after stenting might contribute to restenosis/reocclusion. To test the hypothesis that WSS is impaired along the stented SFA segment, we studied the profile of WSS along the femoro-popliteal axis after stent placement in a crosssectional design. Methods: Eighty-seven patients with PAD (89 limbs) were included one day after stenting of the SFA. Flow velocities (peak and mean) and vessel diameter were measured by duplex ultrasound in five predefined segments along the femoro-popliteal axis, at rest and after exercise (30 toe raises); WSS (peak and mean) was calculated from flow velocities, vessel diameter and whole blood viscosity. Results: WSS progressively declined along the stented segment at rest (peak WSS, p < 0.0001; mean WSS, p < 0.05); after exercise, WSS increased in all segments (all p < 0.001), but, again, progressively declined along the stent (peak WSS, p < 0.0001; mean WSS, p < 0.05). The internal vessel diameter remained unchanged after exercise in the stented and in the non-stented parts of the femoro-popliteal axis (all p > 0.05). Conclusion: In PAD patients with SFA stenting WSS is impaired along the femoro-popliteal axis. The consequences of this finding in terms of local effects on the vessel wall that might favor restenosis/ reocclusion needs further investigation. Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Wall shear stress Superficial femoral artery Peripheral arterial disease Stent Endovascular treatment Blood viscosity
1. Introduction Wall shear stress (WSS) is the frictional force that flowing blood exerts on the vascular endothelium [1]. Endothelial cells sense variations of WSS and subsequently adapt vascular lumen dimensions via biomechanical transduction mechanisms [2]. Segmental disturbances of WSS potentially provoke endothelial dysfunction and subsequent vessel wall thickening [2e6]. In particular, non-laminar, disturbed flow associated with low WSS increases the regional expression of vascular adhesion molecules and enhances transmigration of inflammatory cells into the arterial vessel wall, which promotes the atherosclerotic process [4,7].
* Corresponding author. Division of Angiology, Department of Medicine II, Medical University of Vienna, Waehringer Gürtel 18e20, Ae1090 Vienna, Austria. Tel.: þ43 1 40 400 4670; fax: þ43 1 40 400 4665. E-mail address: [email protected] (R. Koppensteiner). 0021-9150/$ e see front matter Ó 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.035
Previously, we have demonstrated that WSS in the common carotid artery is decreased both in patients with symptomatic peripheral arterial disease (PAD) and in patients with abdominal aortic aneurysm [8]. As common clinical manifestation of atherosclerosis PAD preferably affects the Hunter’s canal of the superficial femoral artery (SFA). In healthy adults, we found that WSS does not vary along the SFA at rest [9]; during exercise, however, the increase of WSS was observed to be less pronounced within the Hunter’s canal, which might contribute to the susceptibility of this particular arterial segment to the emergence of atherosclerotic lesions. For revascularization of obstructive SFA disease endovascular stenting has become a common practice in recent years. Although much effort has been made to improve stent-design and -material, patients still face unsatisfactorily high restenosis rates following SFA stenting, though [10,11]. Stent insertion unavoidably causes vascular injury, which consequently promotes neointimal hyperplasia [12]. Apart from promoting neointimal hyperplasia and vascular remodeling, stent implantation might alter the profile of
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WSS along the respective vessels, especially along the stented segment. Previous data on vascular hemodynamics in the coronary circulation suggest an impact of stenting on local shear forces, which has further been linked to intimal thickening [13,14]. Whether and to what extent long-segment stentingeas it is increasingly performed in the peripheral circulationemight affect WSS in the lower limbs has not been investigated before. Thus, the primary aim of the present study was to assess WSS (peak and mean) along the SFA one day after stenting to test the hypothesis that stent placement affects the profile of WSS along the femoro-popliteal axis. Further, we were interested to study the WSS after stent placement in relation to clinical and laboratory characteristics. 2. Patients and methods 2.1. Inclusion criteria From May 2006 until October 2007 consecutive PAD patients undergoing long-segment stenting of the SFA were eligible for the study. The inclusion criterion was successful stenting of the SFA, defined as the absence of >30% residual stenosis demonstrated by duplex-sonography of the femoro-popliteal segment the day after the interventional procedure. Any hemodynamically relevant obstruction of the ipsilateral iliac arteries had to be revascularized within the same endovascular procedure or in a separate procedure before SFA stenting. Regarding the infrapopliteal arteries at least a one-vessel run-off was mandatory. Exclusion criteria were a residual stenosis >30% of the target lesion as well as a flow limiting dissection or the presence of an untreated >50% stenosis of the ipsilateral femoro-popliteal axis, further, unability to perform 30 toe raises due to concomitant cardiac or pulmonary disease, uncontrolled blood pressure, heart rate >100 bpm or restrictions of the musculoskeletal system. The study was performed according to the recommendations of the Declaration of Helsinki and the protocol was approved by the institutional ethics committee. Written informed consent was obtained in all patients before inclusion. 2.2. Clinical surveillance Before the revascularization procedure all patients routinely underwent a complete clinical examination and routine laboratory tests. Patients were classified according to Rutherford categories for PAD. Demographic data including patients’ age, sex, body mass index (BMI), smoking habits and each patient’s medication were systematically recorded. Systolic and diastolic blood pressures were measured in a supine position on both arms using the average of both measurements for further analyses. In all patients anklebrachial-index (ABI) measurements were obtained before and one day after the revascularization. Before revascularization duplex scans of the iliac, femoro-popliteal and the proximal infrapopliteal arteries were performed to identify the target lesion as well as any in- or outflow obstruction. In cases of inconclusive duplex results, magnetic resonance angiography or computed tomography angiography was additionally performed. Prior to the revascularization, medical therapy was optimized in all patients according to current recommendations [15,16]. At least one antiplatelet medication, usually aspirin (100 mg daily), was started at the institutional outpatient clinic before admission to the hospital for the endovascular procedure. In patients who were not on clopidogrel (75 mg daily) at least two days prior to stent implantation, a loading dose of 300 mg was given ahead of the intervention. Following stenting a dual antiplatelet therapy was installed for three months followed by an indefinite single
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antiplatelet medication. One day after stenting all patients underwent duplex scans of the puncture site and the entire femoropopliteal axis of the treated limb. 2.3. Stenting procedure Access to the target vessel was achieved percutaneously by an antegrade 4F sheath or via a retrograde approach using a 6F “crossover” sheath. After insertion of the sheath an intravenous bolus of 3000e5000 units of heparin was administered. The femoro-popliteal axis and its run-off vessels were examined by digital subtraction angiography. After precise documentation of the target lesion within the femoro-popliteal axis dilation was performed by gradual balloon inflation. If no satisfying result could be achieved by plain balloon angioplasty of the SFA, one or more serially connected, self-expanding, bare-metal nitinol stents were implanted. In case of an ipsilateral iliac artery stenosis an iliac angioplasty was performed prior to or immediately after stenting of the SFA. The final result was documented by digital subtraction angiography, and the patency status of infrapopliteal run-off vessels was documented in all patients. All endovascular procedures were performed by the same two experienced interventionists (M.E.G., A.W.E., acknowledgment section). 2.4. Duplex ultrasound Duplex ultrasound was performed prior to revascularization and one day after the procedure in a quiet room with a constant room temperature (22e24 ) after an acclimatization period of 15 min in a supine position. All duplex scans were performed by the same trained operator (O.S.) using Acuson machines [Acuson XP 128 or Acuson Sequoia 512 (both Siemens, Erlangen, Germany)] and a 7.5 MHz linear transducer probe. A stenosis was graded using the peak systolic velocity ratio (PVR), which was defined as the ratio of the peak systolic velocity (PSV) in the stenosis divided by the PSV in the preceding normal segment. A PVR 2.4 was defined as a stenosis >50 percent [17]. Routinely, the iliac arteries, the femoro-popliteal axis and the proximal infrapopliteal arteries were scanned to exclude any residual stenosis of the target vessel or a hemodynamically relevant stenosis of the in- and outflow vessels. For calculation of pWSS and mWSS PSV, the mean velocity and the internal diameter were recorded in 5 different segments of the femoro-popliteal axis: in the native proximal SFA (distance from the femoral bifurcation SD; 8.1 6.2 cm), at the proximal stent edge (13.1 7.8 cm), in the middle of the stent (17.0 7.0 cm), at the distal stent edge (21.0 6.8 cm) and in the P1 segment of the popliteal artery (37.1 2.3 cm). In each segment the PSV and the mean velocity were determined using the smallest possible sample volume placed in the center of the vessel and by keeping the angle between the ultrasound beam and the longitudinal vessel axis between 45 and 59 . The internal diameter, defined as the distance between the near wall intima-lumen-interface to the far wall lumen-intima-interface, was measured from frozen, longitudinally enlarged images of the respective vessel segment showing the lumen-intima-interface most clearly. Aiming at synchronized determination of vessel diameter and PSV, frozen enlarged images were acquired from the “live mode” during spectral Doppler. Then the “cine mode” allows the determination of the vessel diameter in a PSV-triggered fashion. In each arterial segment the vessel diameter was measured twice in two orthogonal planes, and the mean of these two measurements was calculated. To determine the intra-observer (O.S.) variability of duplex ultrasound examinations of the lower limbs we performed 10 repetitive measurements of the SFA on 3 consecutive days. The
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coefficients of variation were 4.9% for PSV, 11.2% for mean blood flow velocity and 3.9% for the vessel diameter of the SFA (Hunter’s canal). In patients with atrial fibrillation the average of three blood flow velocity measurements was calculated and used for further analyses. First, all measurements were done at rest in a supine position. To assess exercise-induced changes of the WSS patients were instructed to perform 30 toe raises (standing flat-footed and raising the heels off the ground repeatedly). Immediately after the toe raises patients were instructed to take a supine position again to record blood flow velocities and the inner vessel diameter at the previously defined SFA-segments. 2.5. Laboratory measurements Blood was drawn from the antecubital vein for determination of hemoglobin concentration, hematocrit, white blood cell count, platelet count, serum creatinine, total cholesterol, triglycerides, LDL (low-density lipoprotein)-cholesterol and HDL (high-density lipoprotein)-cholesterol and HbA1C (glycated hemoglobin) as well as hs-CRP (high sensitivity C-reactive protein), serum amyloid A and fibrinogen. Kidney function was estimated according to the estimated glomerular filtration rate using the Modification of Diet in Renal Disease formula (eGFRMDRD). For the determination of whole blood viscosity blood was drawn immediately before the duplex-scans one day after stenting. Whole blood viscosity was measured in EDTA blood using a rotational viscometer (Contraves LS 30, Contraves, Switzerland) at a high shear rate (94.5/s) at 37 C. 2.6. Calculation of WSS 2
Peak WSS (pWSS [dynes/cm ]) was calculated using the formula 4 blood viscosity [Poise] PSV [cm/sec]/internal diameter [cm] [18], mean WSS (mWSS [dynes/cm2]) was calculated using the duplex sonographically recorded mean blood velocity replacing PSV in the formula described above. As previously published we investigated the reproducibility of the determination of WSS along the femoro-popliteal axis by duplex ultrasound and thereby found an intrasubject coefficient of variation of 6% [9]. 2.7. Statistical analysis Continuous variables are given as means standard deviations (SD) or medians and interquartile ranges (IQR), categorical variables as counts and percentages. To compare WSS at rest and during exercise we used ManneWhitney U tests, as appropriate. Further, we performed a repeated measures analysis of variance for the variables pWSS and mWSS with the fixed factor location. To investigate the relationship between the percentage changes of pWSS and mWSS along SFA-stents and the parameters stent length, patients’ age, sex, BMI, systolic and diastolic blood pressure, heart rate, presence of atrial fibrillation, the presence of diabetes, hs-CRP, serum amyloid A, fibrinogen, eGFRMDRD and serum creatinine Spearman’s rank-order correlations were calculated. In a second model we included clinical parameters that were related to the percentage change of WSS (peak and mean) as covariate in the repeated measures analysis of variance for the variables pWSS and mWSS. P-values <0.05 were considered to indicate statistical significance. The statistical analyses were done using IBMÒ SPSS Statistics 20.0 for Mac and SAS 9.1.
3. Results Between May 2006 and October 2007 197 consecutive PAD patients were screened for eligibility for the present study at our institution. From these, in accordance with the inclusion criteria, 87 Table 1 Clinical and laboratory characteristics of 87 patients (89 limbs) with peripheral arterial disease (PAD) who underwent stenting of the superficial femoral artery. Female [n] Age [years] Height [m] Weight [kg] BMI [kg/m2] Systolic blood pressure [mmHg] Diastolic blood pressure [mmHg] Heart rate [bpm] Atrial fibrillation [n] Arterial hypertension [n] Dyslipidemia [n] Diabetes mellitus [n] Smoking history [n] PAD Rutherford category (before stenting) [n] Category 0 Category 1 Category 2 Category 3 Category 4 Category 5 Category 6 Chronic kidney disease: categories of eGFRMDRD [n] 60 mL/min/1.73 m2 30e59 mL/min/1.73 m2 15e29 mL/min/1.73 m2 <15 mL/min/1.73 m2 Current medication [n] Aspirin Clopidogrel Vitamin K antagonists Statins ACE-inhibitors/ARB Beta blockers Target lesion length [cm] Total occlusions [n] Vascular access Antegrade approach [n] Retrograde “crossover” approach [n] Number of stents 1 stent [n] 2 serially connected stents [n] 3 serially connected stents [n] 4 serially connected stents [n] 5 serially connected stents [n] Stent length [cm] Whole blood viscosity [mPa.s] Erythrocytes [x103/mL] Hemoglobin [g/dL] Hematocrit [%] Platelets [x103/mL] Leukocytes [x103/mL] Fibrinogen [mg/dL] Hs-CRP [mg/dL] Serum amyloid A [mg/L] HbA1C [%] Creatinine [mg/dL] eGFRMDRD [mL/min/1.73 m2] Total cholesterol [mg/dL] LDL-cholesterol [mg/dL] HDL-cholesterol [mg/dL] Triglycerides [mg/dL]
34 (38.2%) 67.9 10.4 1.69 0.09 75.7 15.8 26.4 4.6 133 18 76 10 70 12 9 (10.3%) 87 (97.8%) 88 (98.9%) 40 (44.9%) 67 (75.3%) 0 0 1 (1.1%) 76 (85.4%) 4 (4.5%) 8 (9%) 0 43 (48.3%) 43 (48.3%) 3 (3.4%) 0 83 (93.3%) 88 (98.9%) 13 (14.6%) 83 (93.3%) 67 (75.3%) 44 (49.4%) 10.7 7.3 45 (50.6%) 25 (28.1%) 64 (71.9%) 45 (50.6%) 32 (36%) 10 (11.2%) 1 (1.1%) 1 (1.1%) 11.9 8.4 4.5 (4, 5.1) 4.4 (4, 4.7) 13.5 (12.4, 14.3) 40 (37.1, 42.5) 229 (183, 266.5) 8 (6.2, 9.7) 423.5 (354.5, 503.5) 0.41 (0.18, 1.1) 10.2 (7.8, 21) 5.9 (5.7, 6.6) 1.1 (0.92, 1.34) 59.4 (49.5, 69.4) 181 (151, 221) 97.1 (76.2, 125.7) 48 (38.5, 61.5) 148.5 (109, 236)
Data are given as absolute counts (þpercentage) or mean standard deviation. BMI, body mass index; eGFRMDRD estimated glomerular filtration rate according to the Modification of Diet in Renal Disease formula; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; Hs-CRP, high sensitivity c-reactive protein; HbA1C, glycated hemoglobin; LDL, low-density lipoprotein; HDL, highdensity lipoprotein.
O. Schlager et al. / Atherosclerosis 233 (2014) 76e82
patients (89 treated limbs) were enrolled. Clinical and laboratory characteristics as well as procedure-related data are shown in Table 1. The mean ABI (SD) of the target limb increased from 0.51 0.17 before to 0.77 0.2 (p < 0.0001) after SFA stenting.
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70.2)% at the proximal stent edge, 39.5 (18.6; 73.6)% in the middle of the stent, 40.9 (15.7; 71.7)% at the distal stent edge and 30.3 (5.9; 73.8)% in the popliteal artery, respectively. The percentage increase did not vary in between femoro-popliteal segments (p ¼ 0.74).
3.1. Peak WSS (pWSS) 3.2. Mean WSS (mWSS) At rest, we observed a decline of pWSS values along the stented SFA-segment (Fig. 1A and Table 2). The median percentage change of pWSS from the proximal stent edge to the distal stent edge was 28.4 (IQR 5; 43.2) %. After exercise, defined as 30 toe raises, pWSS increased in all segments (Table 2). The profile of the distributionedeclining values in the middle and distal stent segmentewas similar to the distribution of pWSS at rest (Fig. 1B, Table 2). The median percentage change of pWSS from rest to exercise was 43.4 (IQR 20; 72.6)% in the native proximal SFA, 34.7 (19.8;
A decline of mWSS was observed along the SFA at rest (p < 0.05; Fig. 1A, Table 2). From the proximal stent edge to the distal stent the median percentage change was 24 (IQR 0.9; 48.6) %. The exercise-induced median percentage change of mWSS was similar in all SFA segments: 23.7 (IQR 12.6; 80.5)% in the native proximal SFA, 39.8 (7.8; 79.4)% at the proximal stent edge, 30.6 (6; 68.6)% in the middle of the stent, 22.8 (9; 69.9)% at the distal stent edge and 22 (9.8; 65.1)% in the popliteal artery (p ¼ 0.47, Table 2). Regarding the distribution pattern along the stented SFA, we observed a
Fig. 1. Peak wall shear stress (pWSS) and mean wall shear stress (mWSS) along the femoro-popliteal axis in 87 patients (89 limbs) with peripheral arterial disease (PAD) and superficial femoral artery (SFA) stenting at rest (A) and after exercise (B).
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O. Schlager et al. / Atherosclerosis 233 (2014) 76e82
Table 2 Peak and mean wall shear stress (WSS) in the superficial femoral artery (SFA) and popliteal artery of 87 patients with peripheral arterial disease following stenting of the SFA (89 limbs). Peak WSS [dynes/cm2] Rest Native SFA Proximal stent edge Middle of the stent Distal stent edge Popliteal artery
41.42 43.6 30.69 28.51 35.3
p-valuea
Mean WSS [dynes/cm2]
Exercise (29.18, (28.18, (23.53, (20.79, (26.91,
51.89) 52.89) 39.52) 37.9) 51.05)
52.46 57.3 43.71 40.29 50.42
p-valuea
Rest <0.0001 <0.0001 <0.0001 0.001 <0.0001
(42.47, 67.59) (44.55, 73.17) (33.8, 56.71) (30.72, 51.39) (37.04, 65.3)
19.75 17.46 15.54 14.49 17.6
Exercise (11.43, 25.73) (10.54, 25.84) (10.36, 20.04) (9.66, 20.06) (11.04, 25.71)
21.12 22.56 19.64 19.17 26.56
(14.25, (14.17, (13.35, (12.37, (16.79,
33.11) 34.09) 26.51) 29.23) 34.36)
0.001 <0.0001 <0.0001 <0.0001 <0.0001
Data are given as median (þinterquartile range). After exercise: measurements were done after 30 toe raises. a Rest vs. exercise.
decline of mWSS in the middle and distal segment of the stent after exercise (Fig. 1B). 3.3. Vessel diameter, blood flow velocity At rest, the vessel diameter was similar in all five segments (p > 0.05); after exercise, the vessel diameter remained unchanged not only in the stented segment, but also in the other parts of the femoro-popliteal axis (all p > 0.05, Table 3). PSV decreased from the proximal stent edge to the distal stent edge at rest (p < 0.0001) and significantly increased in all segments after exercise (all p < 0.001) (Table 3). Mean velocity showed a similar profile at rest and after exercise (Table 3). 3.4. Influencing factors Patients’ age was related to the percentage change of pWSS (r ¼ 0.283, p ¼ 0.009) and mWSS (r ¼ 0.225, p ¼ 0.05) within the stented segment of the SFA. We did not see correlations between the percentage change in pWSS/mWSS and stent length, sex, BMI, systolic and diastolic blood pressure, heart rate, the presence of atrial fibrillation, the presence of diabetes mellitus, the presence of a total occlusion of the target lesion prior to intervention, hs-CRP, serum amyloid A, fibrinogen, serum creatinine and eGFRMDRD, respectively (Table 4). According to the statistically significant correlation between patients’ age and pWSS we included age as covariate into the repeated measures analysis of variance. In this second model we still observed a decline of WSS from the proximal to the distal stent edge (pWSS, p ¼ 0.001; mWSS, p ¼ 0.05). 4. Discussion In the present study we investigated the profile of WSS (peak and mean) along the femoro-popliteal axis in PAD patients after SFA stenting. At rest, we observed a progressive decline of WSS (both, peak and mean) along the stented segment; after exercise,
pWSS and mWSS increased to a similar extent in all segments, but the profile of distribution e a decline along the stent e was similar to the findings at rest. The internal vessel diameter remained unchanged not only in the stented segment, but also in the notstented parts of the femoro-popliteal axis after exercise. In contrast to these findings, pWSS and mWSS do not vary along the femoro-popliteal axis in healthy adults [9]. Accordingly, it seems unlikely that the observed decline of WSS along SFA stents can be attributed to anatomical properties of the SFA, such as vessel length and external compression or traction forces by the surrounding musculature. We therefore suggest that the decrease of pWSS and mWSS is the consequence of the insertion of a relatively rigid stent in an otherwise elastic artery. Notably, the elasticity of the arterial vessel wall influences arterial flow characteristics [19]: vessel wall elasticity enables cyclic distensions and recoils of the artery, which subsequently promotes the characteristic pulsatile flow profile. The transition of blood flow from native to stentede and thereby stiffenedearterial segments considerably affects vascular hemodynamics resulting in a decline of PSV and mean velocity. Furthermore, stent implantation mostly flattens the arterial wall and might additionally straighten the anatomical shape of the artery, especially following long-segment stenting [20]. The changeover of blood flow from a thickened and uneven atherosclerotic vessel wall to an arterial segment, which is flattened after stenting, potentially provokes turbulent and oscillatory flow profiles. Oscillatory flow profiles decelerate peak velocities and shear forces in arterial segments located further downstream. These local variations of vascular hemodynamics might explain the progressive decline in blood flow velocity and consequently the decline in WSS along the stented segment. As well documented, outcome after endovascular revascularization of the lower extremities is dependent on several risk factors [21]. However, we found no relevant correlations between risk factors such as obesity, dyslipidemia and systemic inflammation and the course of WSS. Analyzing the associations between patients’ demographic characteristics and the course of WSS we found that the percentage decrease of WSS along the stented
Table 3 Peak systolic velocity (PSV), mean velocity and diameter of the superficial femoral artery (SFA) and popliteal artery of 87 patients with peripheral arterial disease (PAD) following stenting of the SFA (89 limbs). p-valuea
PSV [m/s] Rest Native SFA Proximal stent edge Middle of the stent Distal stent edge Popliteal artery
1.01 1.01 0.81 0.75 0.86
Exercise (0.79, 1.24) (0.8, 1.3) (0.65, 0.98) (0.58, 0.92) (0.67, 1.17)
1.34 1.43 1.11 1.06 1.28
(1.15, (1.17, (0.88, (0.78, (0.92,
Mean velocity [m/s] Rest
1.78) 1.77) 1.43) 1.29) 1.49)
Data are given as median (þinterquartile range). After exercise: measurements were done after 30 toe raises. a Rest vs. exercise.
<0.0001 <0.0001 <0.0001 <0.0001 <0.0001
0.47 0.45 0.38 0.33 0.45
p-valuea
Diameter [mm] Rest
Exercise
0.002 0.001 0.006 0.001 <0.0001
4.6 4.5 4.8 4.7 4.4
4.7 4.7 4.7 4.7 4.5
Exercise (0.32, 0.60) (0.29, 0.61) (0.3, 0.48) (0.27, 0.52) (0.28, 0.63)
0.58 0.58 0.51 0.53 0.64
(0.41, (0.38, (0.36, (0.33, (0.43,
0.76) 0.82) 0.63) 0.73) 0.84)
(4, 5.2) (4.2, 5.1) (4.2, 5.2) (4.3, 5.1) (4, 4.9)
p-valuea
(4.2, (4.1, (4.3, (4.3, (4.1,
5.1) 5) 5) 5.2) 5.2)
0.39 0.45 0.33 0.83 0.55
O. Schlager et al. / Atherosclerosis 233 (2014) 76e82 Table 4 Correlations between the percentage decline of wall shear stress (WSS) and clinical characteristics of 87 patients with PAD (Spearman rho correlation coefficients). Percentage decline of
Sex (female ¼ 1/male ¼ 0) Age BMI Systolic blood pressure Diastolic blood pressure Heart rate Atrial fibrillation (y ¼ 1/n ¼ 0) Arterial hypertension (y ¼ 1/n ¼ 0) Dyslipidemia (y ¼ 1/n ¼ 0) Diabetes mellitus (y ¼ 1/n ¼ 0) Smoking history (y ¼ 1/n ¼ 0) Occlusiona (y ¼ 1/n ¼ 0) Stent length Fibrinogen Hs-CRP Serum amyloid A Creatinine eGFRMDRD
Peak WSS
mean WSS
0.15 0.283* 0.157 0.026 0.022 0.046 0.108 0.085 0.066 0.005 0.19 0.166 0.063 0.003 0.101 0.087 0.099 0.087
0.114 0.225** 0.21 0.046 0.036 0.159 0.079 0.1 0.075 0.051 0.06 0.091 0.215 0.047 0.3 0.3 0.029 0.025
BMI, body mass index; Hs-CRP, high sensitivity c-reactive protein; eGFRMDRD estimated glomerular filtration rate according to the Modification of Diet in Renal Disease formula. *p < 0.05; **p ¼ 0.05. a Target lesion occlusion prior to intervention.
segment was inversely related to patients’ age. This might be attributed to a generalized loss of arterial elasticity in elderly people, which consequently affects vascular hemodynamics [22]. The implantation of a rigid nitinol stent in a preexisting stiffened arterial system might have less impact on vascular hemodynamics than in younger patients. Nevertheless, we aimed to account for the potential impact of age and included the factor age as covariate into the repeated measures analysis of variance. Thereby, we still observed a statistically significant decline of pWSS, indicating that the stent itself might play a major role. Comparing the profiles of pWSS and mWSS, the percentage decrease of mWSS along the stent was less pronounced. Mean velocity e as automatically determined by duplex ultrasound machines e reflects mean frequencies among the recorded variations of Doppler signal amplitudes [23]. High spectral Doppler frequencies, as they may especially occur along the native atherosclerotic SFA, are excluded from mean velocity values thus explaining the slightly smaller decrease of mWSS within the stent. Experimental data suggest that low WSS is correlated with a higher degree of intimal hyperplasia within a stented region [24]. This has been confirmed in a small in vivo study in patients with coronary artery lesions treated with stents, in which low WSS was associated with neointimal thickness [14]. In contrast, increased WSS has been shown to lead to a reduction of neointimal hyperplasia, inflammation and injury in an experimental setting of stented rabbit external iliac arteries [25]. In the SFA, the development of stenting-induced neointimal hyperplasia has its peak within the first six months after stent implantation. It eventually remains to be proven in longitudinal studies in humans that low WSS values at the distal stent edges of SFA stentsewhich are predilection sites for in-stent restenosis e may promote intimal hyperplasia and pathophysiological mechanisms that lead to the development of restenosis. After 30 toe-raises, we found an increase in pWSS and mWSS in all femoro-popliteal segments. The change of femoro-popliteal WSS primarily refers to an increase of flow velocities, while vessel diameters did not change upon exercise. Comparing the extent of the increase in WSS that we observed in the present study
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with previous data obtained in healthy adults [9], we found that exercise-induced changes in WSS are more pronounced in healthy subjects than in PAD patients. This finding also reflects the disturbed hemodynamic conditions in the SFA after stenting: the reduced potential for exercise-induced increase in WSS might further adversely affect the expression of the endothelial nitric oxide synthase (eNOS) and the NO bioavailability in PAD patients [26]. The present study has to be viewed in the light of its strengths and limitations: it has to be acknowledged that we referred to Poiseuille’s law for the calculation of WSS assuming that the crosssection of the respective vascular segment is circular. Although the calculation of WSSeas it has been applied in this investigationehas been established in several studies before, there might be a confounding by aberrations of a circular cross-section of the respective vessels [8,9,18,27]. Importantly, we only included patients after successful stenting without residual lumen narrowing in the stented segment and in the in- and outflow arterial segments, as demonstrated by duplex sonography. Further, we are aware of the moderate number of patients of the present study. However, we were able to demonstrate a statistically significant decline of pWSS and mWSS along the stented segment. Whether a larger number of patients would have revealed additional information about the relation between WSS and clinical and laboratory characteristics remains to be established. Importantly, the major strength of the present study warrants mention: to our knowledge, the impact of stenting in the SFA on vascular hemodynamics has not been investigated before in a clinical setting. Focusing on the translational value of our findings, we suggest that the rigidity of bare-metal nitinol stents, as they were solely used in this study, plays a decisive role in altered vascular hemodynamics. Whether alternative stent materials, such as bioresorbable stents, would have less detrimental effects on the WSS profile along the SFA, remains speculative. As this study has no longitudinal design it has to be emphasized that the present study does not allow drawing conclusions on a potential relation between the WSS profile after stenting and the development of in-stent restenosis in the long-term. It still needs further investigations to clarify whether theseein comparison with healthy subjects e severely altered hemodynamic conditions in a stented SFA contribute to the development of in-stent restenosis/ reocclusion. In conclusion, SFA stenting is associated with a decline of pWSS and mWSS along the stented segment at rest and after exercise; the internal vessel diameter remains unchanged after exercise in the stented and in the non-stented parts of the femoro-popliteal axis. The consequences of this finding in terms of local effects on the vessel wall that might favor restenosis/reocclusion needs further investigation. Funding None. Conflict of interest None declared. Acknowledgments The authors are indebted to Dr. Andrea Willfort-Ehringer and Dr. Michael Gschwandtner, who collaboratively performed all endovascular procedures.
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Wall shear stress in the stented superficial femoral artery in peripheral arterial disease Oliver Schlager a, Sonja Zehetmayer b, Daniela Seidinger a, Bernd van der Loo a, Renate Koppensteiner a, * a b
Department of Medicine II, Division of Angiology, Medical University of Vienna, Vienna, Austria Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 July 2013 Received in revised form 14 November 2013 Accepted 13 December 2013 Available online 4 January 2014
Objective: Local changes in wall shear stress (WSS) contribute to vascular wall thickening and subsequent stenosis. Restenosis after stenting is a major concern, especially in the superficial femoral artery (SFA) of patients with peripheral arterial disease (PAD). Local alterations in WSS after stenting might contribute to restenosis/reocclusion. To test the hypothesis that WSS is impaired along the stented SFA segment, we studied the profile of WSS along the femoro-popliteal axis after stent placement in a crosssectional design. Methods: Eighty-seven patients with PAD (89 limbs) were included one day after stenting of the SFA. Flow velocities (peak and mean) and vessel diameter were measured by duplex ultrasound in five predefined segments along the femoro-popliteal axis, at rest and after exercise (30 toe raises); WSS (peak and mean) was calculated from flow velocities, vessel diameter and whole blood viscosity. Results: WSS progressively declined along the stented segment at rest (peak WSS, p < 0.0001; mean WSS, p < 0.05); after exercise, WSS increased in all segments (all p < 0.001), but, again, progressively declined along the stent (peak WSS, p < 0.0001; mean WSS, p < 0.05). The internal vessel diameter remained unchanged after exercise in the stented and in the non-stented parts of the femoro-popliteal axis (all p > 0.05). Conclusion: In PAD patients with SFA stenting WSS is impaired along the femoro-popliteal axis. The consequences of this finding in terms of local effects on the vessel wall that might favor restenosis/ reocclusion needs further investigation. Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Wall shear stress Superficial femoral artery Peripheral arterial disease Stent Endovascular treatment Blood viscosity
1. Introduction Wall shear stress (WSS) is the frictional force that flowing blood exerts on the vascular endothelium [1]. Endothelial cells sense variations of WSS and subsequently adapt vascular lumen dimensions via biomechanical transduction mechanisms [2]. Segmental disturbances of WSS potentially provoke endothelial dysfunction and subsequent vessel wall thickening [2e6]. In particular, non-laminar, disturbed flow associated with low WSS increases the regional expression of vascular adhesion molecules and enhances transmigration of inflammatory cells into the arterial vessel wall, which promotes the atherosclerotic process [4,7].
* Corresponding author. Division of Angiology, Department of Medicine II, Medical University of Vienna, Waehringer Gürtel 18e20, Ae1090 Vienna, Austria. Tel.: þ43 1 40 400 4670; fax: þ43 1 40 400 4665. E-mail address: [email protected] (R. Koppensteiner). 0021-9150/$ e see front matter Ó 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.035
Previously, we have demonstrated that WSS in the common carotid artery is decreased both in patients with symptomatic peripheral arterial disease (PAD) and in patients with abdominal aortic aneurysm [8]. As common clinical manifestation of atherosclerosis PAD preferably affects the Hunter’s canal of the superficial femoral artery (SFA). In healthy adults, we found that WSS does not vary along the SFA at rest [9]; during exercise, however, the increase of WSS was observed to be less pronounced within the Hunter’s canal, which might contribute to the susceptibility of this particular arterial segment to the emergence of atherosclerotic lesions. For revascularization of obstructive SFA disease endovascular stenting has become a common practice in recent years. Although much effort has been made to improve stent-design and -material, patients still face unsatisfactorily high restenosis rates following SFA stenting, though [10,11]. Stent insertion unavoidably causes vascular injury, which consequently promotes neointimal hyperplasia [12]. Apart from promoting neointimal hyperplasia and vascular remodeling, stent implantation might alter the profile of
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WSS along the respective vessels, especially along the stented segment. Previous data on vascular hemodynamics in the coronary circulation suggest an impact of stenting on local shear forces, which has further been linked to intimal thickening [13,14]. Whether and to what extent long-segment stentingeas it is increasingly performed in the peripheral circulationemight affect WSS in the lower limbs has not been investigated before. Thus, the primary aim of the present study was to assess WSS (peak and mean) along the SFA one day after stenting to test the hypothesis that stent placement affects the profile of WSS along the femoro-popliteal axis. Further, we were interested to study the WSS after stent placement in relation to clinical and laboratory characteristics. 2. Patients and methods 2.1. Inclusion criteria From May 2006 until October 2007 consecutive PAD patients undergoing long-segment stenting of the SFA were eligible for the study. The inclusion criterion was successful stenting of the SFA, defined as the absence of >30% residual stenosis demonstrated by duplex-sonography of the femoro-popliteal segment the day after the interventional procedure. Any hemodynamically relevant obstruction of the ipsilateral iliac arteries had to be revascularized within the same endovascular procedure or in a separate procedure before SFA stenting. Regarding the infrapopliteal arteries at least a one-vessel run-off was mandatory. Exclusion criteria were a residual stenosis >30% of the target lesion as well as a flow limiting dissection or the presence of an untreated >50% stenosis of the ipsilateral femoro-popliteal axis, further, unability to perform 30 toe raises due to concomitant cardiac or pulmonary disease, uncontrolled blood pressure, heart rate >100 bpm or restrictions of the musculoskeletal system. The study was performed according to the recommendations of the Declaration of Helsinki and the protocol was approved by the institutional ethics committee. Written informed consent was obtained in all patients before inclusion. 2.2. Clinical surveillance Before the revascularization procedure all patients routinely underwent a complete clinical examination and routine laboratory tests. Patients were classified according to Rutherford categories for PAD. Demographic data including patients’ age, sex, body mass index (BMI), smoking habits and each patient’s medication were systematically recorded. Systolic and diastolic blood pressures were measured in a supine position on both arms using the average of both measurements for further analyses. In all patients anklebrachial-index (ABI) measurements were obtained before and one day after the revascularization. Before revascularization duplex scans of the iliac, femoro-popliteal and the proximal infrapopliteal arteries were performed to identify the target lesion as well as any in- or outflow obstruction. In cases of inconclusive duplex results, magnetic resonance angiography or computed tomography angiography was additionally performed. Prior to the revascularization, medical therapy was optimized in all patients according to current recommendations [15,16]. At least one antiplatelet medication, usually aspirin (100 mg daily), was started at the institutional outpatient clinic before admission to the hospital for the endovascular procedure. In patients who were not on clopidogrel (75 mg daily) at least two days prior to stent implantation, a loading dose of 300 mg was given ahead of the intervention. Following stenting a dual antiplatelet therapy was installed for three months followed by an indefinite single
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antiplatelet medication. One day after stenting all patients underwent duplex scans of the puncture site and the entire femoropopliteal axis of the treated limb. 2.3. Stenting procedure Access to the target vessel was achieved percutaneously by an antegrade 4F sheath or via a retrograde approach using a 6F “crossover” sheath. After insertion of the sheath an intravenous bolus of 3000e5000 units of heparin was administered. The femoro-popliteal axis and its run-off vessels were examined by digital subtraction angiography. After precise documentation of the target lesion within the femoro-popliteal axis dilation was performed by gradual balloon inflation. If no satisfying result could be achieved by plain balloon angioplasty of the SFA, one or more serially connected, self-expanding, bare-metal nitinol stents were implanted. In case of an ipsilateral iliac artery stenosis an iliac angioplasty was performed prior to or immediately after stenting of the SFA. The final result was documented by digital subtraction angiography, and the patency status of infrapopliteal run-off vessels was documented in all patients. All endovascular procedures were performed by the same two experienced interventionists (M.E.G., A.W.E., acknowledgment section). 2.4. Duplex ultrasound Duplex ultrasound was performed prior to revascularization and one day after the procedure in a quiet room with a constant room temperature (22e24 ) after an acclimatization period of 15 min in a supine position. All duplex scans were performed by the same trained operator (O.S.) using Acuson machines [Acuson XP 128 or Acuson Sequoia 512 (both Siemens, Erlangen, Germany)] and a 7.5 MHz linear transducer probe. A stenosis was graded using the peak systolic velocity ratio (PVR), which was defined as the ratio of the peak systolic velocity (PSV) in the stenosis divided by the PSV in the preceding normal segment. A PVR 2.4 was defined as a stenosis >50 percent [17]. Routinely, the iliac arteries, the femoro-popliteal axis and the proximal infrapopliteal arteries were scanned to exclude any residual stenosis of the target vessel or a hemodynamically relevant stenosis of the in- and outflow vessels. For calculation of pWSS and mWSS PSV, the mean velocity and the internal diameter were recorded in 5 different segments of the femoro-popliteal axis: in the native proximal SFA (distance from the femoral bifurcation SD; 8.1 6.2 cm), at the proximal stent edge (13.1 7.8 cm), in the middle of the stent (17.0 7.0 cm), at the distal stent edge (21.0 6.8 cm) and in the P1 segment of the popliteal artery (37.1 2.3 cm). In each segment the PSV and the mean velocity were determined using the smallest possible sample volume placed in the center of the vessel and by keeping the angle between the ultrasound beam and the longitudinal vessel axis between 45 and 59 . The internal diameter, defined as the distance between the near wall intima-lumen-interface to the far wall lumen-intima-interface, was measured from frozen, longitudinally enlarged images of the respective vessel segment showing the lumen-intima-interface most clearly. Aiming at synchronized determination of vessel diameter and PSV, frozen enlarged images were acquired from the “live mode” during spectral Doppler. Then the “cine mode” allows the determination of the vessel diameter in a PSV-triggered fashion. In each arterial segment the vessel diameter was measured twice in two orthogonal planes, and the mean of these two measurements was calculated. To determine the intra-observer (O.S.) variability of duplex ultrasound examinations of the lower limbs we performed 10 repetitive measurements of the SFA on 3 consecutive days. The
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coefficients of variation were 4.9% for PSV, 11.2% for mean blood flow velocity and 3.9% for the vessel diameter of the SFA (Hunter’s canal). In patients with atrial fibrillation the average of three blood flow velocity measurements was calculated and used for further analyses. First, all measurements were done at rest in a supine position. To assess exercise-induced changes of the WSS patients were instructed to perform 30 toe raises (standing flat-footed and raising the heels off the ground repeatedly). Immediately after the toe raises patients were instructed to take a supine position again to record blood flow velocities and the inner vessel diameter at the previously defined SFA-segments. 2.5. Laboratory measurements Blood was drawn from the antecubital vein for determination of hemoglobin concentration, hematocrit, white blood cell count, platelet count, serum creatinine, total cholesterol, triglycerides, LDL (low-density lipoprotein)-cholesterol and HDL (high-density lipoprotein)-cholesterol and HbA1C (glycated hemoglobin) as well as hs-CRP (high sensitivity C-reactive protein), serum amyloid A and fibrinogen. Kidney function was estimated according to the estimated glomerular filtration rate using the Modification of Diet in Renal Disease formula (eGFRMDRD). For the determination of whole blood viscosity blood was drawn immediately before the duplex-scans one day after stenting. Whole blood viscosity was measured in EDTA blood using a rotational viscometer (Contraves LS 30, Contraves, Switzerland) at a high shear rate (94.5/s) at 37 C. 2.6. Calculation of WSS 2
Peak WSS (pWSS [dynes/cm ]) was calculated using the formula 4 blood viscosity [Poise] PSV [cm/sec]/internal diameter [cm] [18], mean WSS (mWSS [dynes/cm2]) was calculated using the duplex sonographically recorded mean blood velocity replacing PSV in the formula described above. As previously published we investigated the reproducibility of the determination of WSS along the femoro-popliteal axis by duplex ultrasound and thereby found an intrasubject coefficient of variation of 6% [9]. 2.7. Statistical analysis Continuous variables are given as means standard deviations (SD) or medians and interquartile ranges (IQR), categorical variables as counts and percentages. To compare WSS at rest and during exercise we used ManneWhitney U tests, as appropriate. Further, we performed a repeated measures analysis of variance for the variables pWSS and mWSS with the fixed factor location. To investigate the relationship between the percentage changes of pWSS and mWSS along SFA-stents and the parameters stent length, patients’ age, sex, BMI, systolic and diastolic blood pressure, heart rate, presence of atrial fibrillation, the presence of diabetes, hs-CRP, serum amyloid A, fibrinogen, eGFRMDRD and serum creatinine Spearman’s rank-order correlations were calculated. In a second model we included clinical parameters that were related to the percentage change of WSS (peak and mean) as covariate in the repeated measures analysis of variance for the variables pWSS and mWSS. P-values <0.05 were considered to indicate statistical significance. The statistical analyses were done using IBMÒ SPSS Statistics 20.0 for Mac and SAS 9.1.
3. Results Between May 2006 and October 2007 197 consecutive PAD patients were screened for eligibility for the present study at our institution. From these, in accordance with the inclusion criteria, 87 Table 1 Clinical and laboratory characteristics of 87 patients (89 limbs) with peripheral arterial disease (PAD) who underwent stenting of the superficial femoral artery. Female [n] Age [years] Height [m] Weight [kg] BMI [kg/m2] Systolic blood pressure [mmHg] Diastolic blood pressure [mmHg] Heart rate [bpm] Atrial fibrillation [n] Arterial hypertension [n] Dyslipidemia [n] Diabetes mellitus [n] Smoking history [n] PAD Rutherford category (before stenting) [n] Category 0 Category 1 Category 2 Category 3 Category 4 Category 5 Category 6 Chronic kidney disease: categories of eGFRMDRD [n] 60 mL/min/1.73 m2 30e59 mL/min/1.73 m2 15e29 mL/min/1.73 m2 <15 mL/min/1.73 m2 Current medication [n] Aspirin Clopidogrel Vitamin K antagonists Statins ACE-inhibitors/ARB Beta blockers Target lesion length [cm] Total occlusions [n] Vascular access Antegrade approach [n] Retrograde “crossover” approach [n] Number of stents 1 stent [n] 2 serially connected stents [n] 3 serially connected stents [n] 4 serially connected stents [n] 5 serially connected stents [n] Stent length [cm] Whole blood viscosity [mPa.s] Erythrocytes [x103/mL] Hemoglobin [g/dL] Hematocrit [%] Platelets [x103/mL] Leukocytes [x103/mL] Fibrinogen [mg/dL] Hs-CRP [mg/dL] Serum amyloid A [mg/L] HbA1C [%] Creatinine [mg/dL] eGFRMDRD [mL/min/1.73 m2] Total cholesterol [mg/dL] LDL-cholesterol [mg/dL] HDL-cholesterol [mg/dL] Triglycerides [mg/dL]
34 (38.2%) 67.9 10.4 1.69 0.09 75.7 15.8 26.4 4.6 133 18 76 10 70 12 9 (10.3%) 87 (97.8%) 88 (98.9%) 40 (44.9%) 67 (75.3%) 0 0 1 (1.1%) 76 (85.4%) 4 (4.5%) 8 (9%) 0 43 (48.3%) 43 (48.3%) 3 (3.4%) 0 83 (93.3%) 88 (98.9%) 13 (14.6%) 83 (93.3%) 67 (75.3%) 44 (49.4%) 10.7 7.3 45 (50.6%) 25 (28.1%) 64 (71.9%) 45 (50.6%) 32 (36%) 10 (11.2%) 1 (1.1%) 1 (1.1%) 11.9 8.4 4.5 (4, 5.1) 4.4 (4, 4.7) 13.5 (12.4, 14.3) 40 (37.1, 42.5) 229 (183, 266.5) 8 (6.2, 9.7) 423.5 (354.5, 503.5) 0.41 (0.18, 1.1) 10.2 (7.8, 21) 5.9 (5.7, 6.6) 1.1 (0.92, 1.34) 59.4 (49.5, 69.4) 181 (151, 221) 97.1 (76.2, 125.7) 48 (38.5, 61.5) 148.5 (109, 236)
Data are given as absolute counts (þpercentage) or mean standard deviation. BMI, body mass index; eGFRMDRD estimated glomerular filtration rate according to the Modification of Diet in Renal Disease formula; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; Hs-CRP, high sensitivity c-reactive protein; HbA1C, glycated hemoglobin; LDL, low-density lipoprotein; HDL, highdensity lipoprotein.
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patients (89 treated limbs) were enrolled. Clinical and laboratory characteristics as well as procedure-related data are shown in Table 1. The mean ABI (SD) of the target limb increased from 0.51 0.17 before to 0.77 0.2 (p < 0.0001) after SFA stenting.
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70.2)% at the proximal stent edge, 39.5 (18.6; 73.6)% in the middle of the stent, 40.9 (15.7; 71.7)% at the distal stent edge and 30.3 (5.9; 73.8)% in the popliteal artery, respectively. The percentage increase did not vary in between femoro-popliteal segments (p ¼ 0.74).
3.1. Peak WSS (pWSS) 3.2. Mean WSS (mWSS) At rest, we observed a decline of pWSS values along the stented SFA-segment (Fig. 1A and Table 2). The median percentage change of pWSS from the proximal stent edge to the distal stent edge was 28.4 (IQR 5; 43.2) %. After exercise, defined as 30 toe raises, pWSS increased in all segments (Table 2). The profile of the distributionedeclining values in the middle and distal stent segmentewas similar to the distribution of pWSS at rest (Fig. 1B, Table 2). The median percentage change of pWSS from rest to exercise was 43.4 (IQR 20; 72.6)% in the native proximal SFA, 34.7 (19.8;
A decline of mWSS was observed along the SFA at rest (p < 0.05; Fig. 1A, Table 2). From the proximal stent edge to the distal stent the median percentage change was 24 (IQR 0.9; 48.6) %. The exercise-induced median percentage change of mWSS was similar in all SFA segments: 23.7 (IQR 12.6; 80.5)% in the native proximal SFA, 39.8 (7.8; 79.4)% at the proximal stent edge, 30.6 (6; 68.6)% in the middle of the stent, 22.8 (9; 69.9)% at the distal stent edge and 22 (9.8; 65.1)% in the popliteal artery (p ¼ 0.47, Table 2). Regarding the distribution pattern along the stented SFA, we observed a
Fig. 1. Peak wall shear stress (pWSS) and mean wall shear stress (mWSS) along the femoro-popliteal axis in 87 patients (89 limbs) with peripheral arterial disease (PAD) and superficial femoral artery (SFA) stenting at rest (A) and after exercise (B).
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Table 2 Peak and mean wall shear stress (WSS) in the superficial femoral artery (SFA) and popliteal artery of 87 patients with peripheral arterial disease following stenting of the SFA (89 limbs). Peak WSS [dynes/cm2] Rest Native SFA Proximal stent edge Middle of the stent Distal stent edge Popliteal artery
41.42 43.6 30.69 28.51 35.3
p-valuea
Mean WSS [dynes/cm2]
Exercise (29.18, (28.18, (23.53, (20.79, (26.91,
51.89) 52.89) 39.52) 37.9) 51.05)
52.46 57.3 43.71 40.29 50.42
p-valuea
Rest <0.0001 <0.0001 <0.0001 0.001 <0.0001
(42.47, 67.59) (44.55, 73.17) (33.8, 56.71) (30.72, 51.39) (37.04, 65.3)
19.75 17.46 15.54 14.49 17.6
Exercise (11.43, 25.73) (10.54, 25.84) (10.36, 20.04) (9.66, 20.06) (11.04, 25.71)
21.12 22.56 19.64 19.17 26.56
(14.25, (14.17, (13.35, (12.37, (16.79,
33.11) 34.09) 26.51) 29.23) 34.36)
0.001 <0.0001 <0.0001 <0.0001 <0.0001
Data are given as median (þinterquartile range). After exercise: measurements were done after 30 toe raises. a Rest vs. exercise.
decline of mWSS in the middle and distal segment of the stent after exercise (Fig. 1B). 3.3. Vessel diameter, blood flow velocity At rest, the vessel diameter was similar in all five segments (p > 0.05); after exercise, the vessel diameter remained unchanged not only in the stented segment, but also in the other parts of the femoro-popliteal axis (all p > 0.05, Table 3). PSV decreased from the proximal stent edge to the distal stent edge at rest (p < 0.0001) and significantly increased in all segments after exercise (all p < 0.001) (Table 3). Mean velocity showed a similar profile at rest and after exercise (Table 3). 3.4. Influencing factors Patients’ age was related to the percentage change of pWSS (r ¼ 0.283, p ¼ 0.009) and mWSS (r ¼ 0.225, p ¼ 0.05) within the stented segment of the SFA. We did not see correlations between the percentage change in pWSS/mWSS and stent length, sex, BMI, systolic and diastolic blood pressure, heart rate, the presence of atrial fibrillation, the presence of diabetes mellitus, the presence of a total occlusion of the target lesion prior to intervention, hs-CRP, serum amyloid A, fibrinogen, serum creatinine and eGFRMDRD, respectively (Table 4). According to the statistically significant correlation between patients’ age and pWSS we included age as covariate into the repeated measures analysis of variance. In this second model we still observed a decline of WSS from the proximal to the distal stent edge (pWSS, p ¼ 0.001; mWSS, p ¼ 0.05). 4. Discussion In the present study we investigated the profile of WSS (peak and mean) along the femoro-popliteal axis in PAD patients after SFA stenting. At rest, we observed a progressive decline of WSS (both, peak and mean) along the stented segment; after exercise,
pWSS and mWSS increased to a similar extent in all segments, but the profile of distribution e a decline along the stent e was similar to the findings at rest. The internal vessel diameter remained unchanged not only in the stented segment, but also in the notstented parts of the femoro-popliteal axis after exercise. In contrast to these findings, pWSS and mWSS do not vary along the femoro-popliteal axis in healthy adults [9]. Accordingly, it seems unlikely that the observed decline of WSS along SFA stents can be attributed to anatomical properties of the SFA, such as vessel length and external compression or traction forces by the surrounding musculature. We therefore suggest that the decrease of pWSS and mWSS is the consequence of the insertion of a relatively rigid stent in an otherwise elastic artery. Notably, the elasticity of the arterial vessel wall influences arterial flow characteristics [19]: vessel wall elasticity enables cyclic distensions and recoils of the artery, which subsequently promotes the characteristic pulsatile flow profile. The transition of blood flow from native to stentede and thereby stiffenedearterial segments considerably affects vascular hemodynamics resulting in a decline of PSV and mean velocity. Furthermore, stent implantation mostly flattens the arterial wall and might additionally straighten the anatomical shape of the artery, especially following long-segment stenting [20]. The changeover of blood flow from a thickened and uneven atherosclerotic vessel wall to an arterial segment, which is flattened after stenting, potentially provokes turbulent and oscillatory flow profiles. Oscillatory flow profiles decelerate peak velocities and shear forces in arterial segments located further downstream. These local variations of vascular hemodynamics might explain the progressive decline in blood flow velocity and consequently the decline in WSS along the stented segment. As well documented, outcome after endovascular revascularization of the lower extremities is dependent on several risk factors [21]. However, we found no relevant correlations between risk factors such as obesity, dyslipidemia and systemic inflammation and the course of WSS. Analyzing the associations between patients’ demographic characteristics and the course of WSS we found that the percentage decrease of WSS along the stented
Table 3 Peak systolic velocity (PSV), mean velocity and diameter of the superficial femoral artery (SFA) and popliteal artery of 87 patients with peripheral arterial disease (PAD) following stenting of the SFA (89 limbs). p-valuea
PSV [m/s] Rest Native SFA Proximal stent edge Middle of the stent Distal stent edge Popliteal artery
1.01 1.01 0.81 0.75 0.86
Exercise (0.79, 1.24) (0.8, 1.3) (0.65, 0.98) (0.58, 0.92) (0.67, 1.17)
1.34 1.43 1.11 1.06 1.28
(1.15, (1.17, (0.88, (0.78, (0.92,
Mean velocity [m/s] Rest
1.78) 1.77) 1.43) 1.29) 1.49)
Data are given as median (þinterquartile range). After exercise: measurements were done after 30 toe raises. a Rest vs. exercise.
<0.0001 <0.0001 <0.0001 <0.0001 <0.0001
0.47 0.45 0.38 0.33 0.45
p-valuea
Diameter [mm] Rest
Exercise
0.002 0.001 0.006 0.001 <0.0001
4.6 4.5 4.8 4.7 4.4
4.7 4.7 4.7 4.7 4.5
Exercise (0.32, 0.60) (0.29, 0.61) (0.3, 0.48) (0.27, 0.52) (0.28, 0.63)
0.58 0.58 0.51 0.53 0.64
(0.41, (0.38, (0.36, (0.33, (0.43,
0.76) 0.82) 0.63) 0.73) 0.84)
(4, 5.2) (4.2, 5.1) (4.2, 5.2) (4.3, 5.1) (4, 4.9)
p-valuea
(4.2, (4.1, (4.3, (4.3, (4.1,
5.1) 5) 5) 5.2) 5.2)
0.39 0.45 0.33 0.83 0.55
O. Schlager et al. / Atherosclerosis 233 (2014) 76e82 Table 4 Correlations between the percentage decline of wall shear stress (WSS) and clinical characteristics of 87 patients with PAD (Spearman rho correlation coefficients). Percentage decline of
Sex (female ¼ 1/male ¼ 0) Age BMI Systolic blood pressure Diastolic blood pressure Heart rate Atrial fibrillation (y ¼ 1/n ¼ 0) Arterial hypertension (y ¼ 1/n ¼ 0) Dyslipidemia (y ¼ 1/n ¼ 0) Diabetes mellitus (y ¼ 1/n ¼ 0) Smoking history (y ¼ 1/n ¼ 0) Occlusiona (y ¼ 1/n ¼ 0) Stent length Fibrinogen Hs-CRP Serum amyloid A Creatinine eGFRMDRD
Peak WSS
mean WSS
0.15 0.283* 0.157 0.026 0.022 0.046 0.108 0.085 0.066 0.005 0.19 0.166 0.063 0.003 0.101 0.087 0.099 0.087
0.114 0.225** 0.21 0.046 0.036 0.159 0.079 0.1 0.075 0.051 0.06 0.091 0.215 0.047 0.3 0.3 0.029 0.025
BMI, body mass index; Hs-CRP, high sensitivity c-reactive protein; eGFRMDRD estimated glomerular filtration rate according to the Modification of Diet in Renal Disease formula. *p < 0.05; **p ¼ 0.05. a Target lesion occlusion prior to intervention.
segment was inversely related to patients’ age. This might be attributed to a generalized loss of arterial elasticity in elderly people, which consequently affects vascular hemodynamics [22]. The implantation of a rigid nitinol stent in a preexisting stiffened arterial system might have less impact on vascular hemodynamics than in younger patients. Nevertheless, we aimed to account for the potential impact of age and included the factor age as covariate into the repeated measures analysis of variance. Thereby, we still observed a statistically significant decline of pWSS, indicating that the stent itself might play a major role. Comparing the profiles of pWSS and mWSS, the percentage decrease of mWSS along the stent was less pronounced. Mean velocity e as automatically determined by duplex ultrasound machines e reflects mean frequencies among the recorded variations of Doppler signal amplitudes [23]. High spectral Doppler frequencies, as they may especially occur along the native atherosclerotic SFA, are excluded from mean velocity values thus explaining the slightly smaller decrease of mWSS within the stent. Experimental data suggest that low WSS is correlated with a higher degree of intimal hyperplasia within a stented region [24]. This has been confirmed in a small in vivo study in patients with coronary artery lesions treated with stents, in which low WSS was associated with neointimal thickness [14]. In contrast, increased WSS has been shown to lead to a reduction of neointimal hyperplasia, inflammation and injury in an experimental setting of stented rabbit external iliac arteries [25]. In the SFA, the development of stenting-induced neointimal hyperplasia has its peak within the first six months after stent implantation. It eventually remains to be proven in longitudinal studies in humans that low WSS values at the distal stent edges of SFA stentsewhich are predilection sites for in-stent restenosis e may promote intimal hyperplasia and pathophysiological mechanisms that lead to the development of restenosis. After 30 toe-raises, we found an increase in pWSS and mWSS in all femoro-popliteal segments. The change of femoro-popliteal WSS primarily refers to an increase of flow velocities, while vessel diameters did not change upon exercise. Comparing the extent of the increase in WSS that we observed in the present study
81
with previous data obtained in healthy adults [9], we found that exercise-induced changes in WSS are more pronounced in healthy subjects than in PAD patients. This finding also reflects the disturbed hemodynamic conditions in the SFA after stenting: the reduced potential for exercise-induced increase in WSS might further adversely affect the expression of the endothelial nitric oxide synthase (eNOS) and the NO bioavailability in PAD patients [26]. The present study has to be viewed in the light of its strengths and limitations: it has to be acknowledged that we referred to Poiseuille’s law for the calculation of WSS assuming that the crosssection of the respective vascular segment is circular. Although the calculation of WSSeas it has been applied in this investigationehas been established in several studies before, there might be a confounding by aberrations of a circular cross-section of the respective vessels [8,9,18,27]. Importantly, we only included patients after successful stenting without residual lumen narrowing in the stented segment and in the in- and outflow arterial segments, as demonstrated by duplex sonography. Further, we are aware of the moderate number of patients of the present study. However, we were able to demonstrate a statistically significant decline of pWSS and mWSS along the stented segment. Whether a larger number of patients would have revealed additional information about the relation between WSS and clinical and laboratory characteristics remains to be established. Importantly, the major strength of the present study warrants mention: to our knowledge, the impact of stenting in the SFA on vascular hemodynamics has not been investigated before in a clinical setting. Focusing on the translational value of our findings, we suggest that the rigidity of bare-metal nitinol stents, as they were solely used in this study, plays a decisive role in altered vascular hemodynamics. Whether alternative stent materials, such as bioresorbable stents, would have less detrimental effects on the WSS profile along the SFA, remains speculative. As this study has no longitudinal design it has to be emphasized that the present study does not allow drawing conclusions on a potential relation between the WSS profile after stenting and the development of in-stent restenosis in the long-term. It still needs further investigations to clarify whether theseein comparison with healthy subjects e severely altered hemodynamic conditions in a stented SFA contribute to the development of in-stent restenosis/ reocclusion. In conclusion, SFA stenting is associated with a decline of pWSS and mWSS along the stented segment at rest and after exercise; the internal vessel diameter remains unchanged after exercise in the stented and in the non-stented parts of the femoro-popliteal axis. The consequences of this finding in terms of local effects on the vessel wall that might favor restenosis/reocclusion needs further investigation. Funding None. Conflict of interest None declared. Acknowledgments The authors are indebted to Dr. Andrea Willfort-Ehringer and Dr. Michael Gschwandtner, who collaboratively performed all endovascular procedures.
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