Journal of Vascular Surgery
Volume 44, Issue 4 , Pages 740-746, October 2006

Early biomechanical changes in lower extremity vein grafts—distinct temporal phases of remodeling and wall stiffness

Presented at the Thirty-second Annual Meeting of The New England Society for Vascular Surgery, Stowe, VT, September 18, 2005.

Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Received 15 February 2006; accepted 6 June 2006. published online 23 August 2006.

Article Outline

Background

The geometric and biomechanical changes that contribute to vein graft remodeling are not well established. We sought to measure patterns of adaptation in lower extremity vein grafts and assess their correlation with clinical outcomes.

Methods

We conducted a prospective, longitudinal study of patients undergoing infrainguinal reconstruction with autogenous conduit. In addition to standard duplex surveillance, lumen diameter (of a defined index segment of the conduit) and pulse wave velocity (PWV) were assessed by ultrasound imaging at surgery and at 1, 3, and 6 months postoperatively. Graft dimensions and wall stiffness were correlated with clinical outcomes.

Results

There were 92 patients and 96 limbs in this study. On average, vein graft lumen diameter increased during the first month of implantation from 0.37 ± .01 cm to 0.45 ± 0.02 cm (mean ± SEM; P = .002), representing a relative change of +21.6% (median ± 14%; range, −31 to +67%) during this period. Of the entire cohort, 72% of grafts demonstrated appreciable dilation of the index segment during the first month. Index segment lumen diameter did not change appreciably beyond 1 month, with the notable exception of arm vein conduits, which showed continued tendency to dilate. PWV increased during the first 6 months (17.2 ± 1.2 m/s to 23.2 ± 2.4 m/s; P = .008), reflecting a nearly 40% increase in conduit stiffness (2.0 ± .6 Mdynes/cm to 3.3 ± .8 Mdynes/cm, P = .01). The greatest relative increase (25%) in PWV occurred from months 1 to 3. Loss of primary patency occurred in 24 cases (19 revisions, 5 occlusions), with a mean reintervention time of 7.6 months. Grafts that demonstrated early positive remodeling (lumen dilatation) had a trend of increased primary patency (P = .08, log rank). Among the grafts that failed, a trend was noted toward greater wall stiffness at 1 month, 2.7 vs 1.5 Mdynes (P = .08).

Conclusion

Vein graft remodeling appears to involve at least two distinct temporal phases. Outward remodeling of the lumen occurs early, and wall stiffness changes occur in a more delayed fashion. Early outward remodeling may be important for successful vein graft adaptation.

 

Veins placed into the arterial circulation as bypass conduits are subjected to pulsatile arterial hemodynamics, resulting in an acute increase in wall shear and tangential stress. Furthermore, all veins used for bypass grafting are subjected to mechanical injury during dissection and ischemia–reperfusion before implantation, triggering an inflammatory reaction.1 The biomechanical adaptation of the vein graft thus takes place within the milieu of a complex injury response. This adaptive process has been characterized from histopathologic specimens and animal models.2, 3, 4 The vein wall thickens and develops a hyperplastic neointima that tends to normalize tangential wall stress.5 Distinct from wall stress, there is evidence that lumen diameter changes occur that may be partly related to shear stress.3, 5, 6

Successful vein bypass grafts will remodel such that these wall structural changes occur while maintaining lumenal caliber,3, 7 allowing for biomechanical stabilization and long-term patency. In 20% to 30% of cases, however, lumen narrowing (usually focal) may occur aggressively within the first 6 to 12 months, leading to reintervention or graft failure. The mechanisms responsible for these divergent early healing patterns are poorly understood.

Serial in vivo assessment of human infrainguinal bypass grafts has been predominantly limited to the context of ultrasound-based surveillance for stenosis,8, 9, 10 with relatively little attention given to the geometric and biomechanical changes of the vein over time.11, 12 In a recent study,13 we reported that lower extremity vein grafts undergo a dramatic increase in wall stiffness during the first 6 months after surgery and confirmed that significant geometric remodeling also occurs within this time frame. In the current investigation, we sought to more clearly define the magnitude, variability, and time course of early vein graft remodeling in a larger cohort of patients as well as the potential relationship of these biomechanical changes to vein graft failure.

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Methods 

Study design 

This was a prospective, longitudinal study of 92 patients (96 grafts) undergoing lower extremity bypass with autogenous vein. Patients were excluded if their infrainguinal reconstruction used nonautogenous conduit (in whole or in part), if they were unlikely to fully comply with the follow-up protocol (eg, due to long-distance travel), or if they were unable to provide informed consent before surgery. The experimental protocol and informed consent for this study was approved by the Brigham and Women’s Hospital Institutional Review Board.

Operating room procedure 

The vein graft configuration used for bypass grafting was left to the discretion of the surgeon and depended on the availability of ipsilateral great saphenous vein (GSV). Our general preference in the absence of ipsilateral GSV was to use contralateral GSV, unless there was significant circulatory compromise in the contralateral limb.14 Failing GSV availability, we used alternative autogenous conduit choices, such as arm vein (cephalic or basilic) or short saphenous vein. All valve lysis was performed with a Mill’s valvulotome. In most cases, veins were tunneled superficially for ease of graft surveillance. If a portion of the vein was tunneled in an anatomic position, however, the index segment was chosen in a superficial portion of the conduit. Study subjects were operated on at the Brigham and Woman’s Hospital by staff vascular surgeons assisted by the vascular fellow or vascular surgery house staff.

At the completion of the vascular reconstruction, routine completion duplex ultrasonography was performed to evaluate for flow disturbances or areas of stenosis. All intraoperative images were obtained on an ATL HDI 3000 scanner (Phillips, Bothell, Wash) with a 10-MHz transducer.

Once the clinical duplex scan was completed, we selected a straight, 5-cm-long, valveless, superficial segment of graft to serve as the index segment for serial postoperative measurements of graft diameter. The index segment was selected far enough away from either anastomosis to minimize turbulent blood flow. The distance between the index segment and the proximal anastomosis as well as another anatomic landmark (eg, scar or tibial tuberosity) was noted to ensure that this same segment of vein could be easily identified for subsequent examinations.

Metallic surgical clips were placed on a nearby side branch as a reference point for imaging. The index segment lumen dimensions were then obtained using a series of M-mode images with a cross-sectional view of the vein graft. Five lumen diameter measurements were taken at each of five, 1-cm incremental locations along the index segment. These 25 measurements were then used to determine the mean lumen diameter of the index segment for that examination.

To determine vein graft stiffness, a pulse wave velocity, PWV (m/s) measurement of the vein graft was obtained as previously reported.13 First, the length of the graft was measured using an umbilical tape, and this length was used for all subsequent PWV calculations. Then, waveforms of the graft were obtained 1 cm distal to the proximal anastomosis and 1 cm proximal to the distal anastomosis. A time delay between the internal ultrasound scan electrocardiograph (ECG) trigger and the foot of the Doppler waveform was measured with the waveform and the ECG tracing simultaneously displayed. PWV was subsequently calculated as the distance between the proximal and distal measurement locations divided by the time difference of the QRS-to-onset of flow waveform at the proximal and distal ends of the graft. At least 10 individual time delays were measured at each location and averaged for this calculation.

A sagittal view of the index segment, accompanied by a gated-Doppler waveform obtained from the graft’s centerline, was recorded for subsequent measurements of mean volume flow and shear stress estimation.

Follow-up imaging protocol 

Postoperative examinations were performed in the Brigham and Women’s Hospital Vascular Lab. All examinations were supervised by a board-certified vascular medicine specialist who is a registered vascular technician (M. G. H.). Clinical follow-up scans for vein graft surveillance were scheduled at 1, 3, 6, 9, and 12 months. Subjects were examined at rest in a supine position to allow normalization of heart rate and blood pressure. Clinical surveillance scans included measurement of ankle–brachial indices and duplex ultrasound scans with peak systolic velocity maps. Once the surveillance protocol was completed, the index segment was identified using the referenced external landmarks or clips placed at the time of surgery. M-mode diameter measurements, PWV, and time averaged flow were obtained and calculated as for the intraoperative imaging study.

Clinical follow-up 

All patients enrolled in the trial were scheduled for clinical follow-up visits with the attending vascular surgeon at 1, 3, 6, 9, and 12 months, consistent with our standard practice. At these time points, the patients underwent a complete vascular exam and were evaluated for clinical or graft-related events. Recorded were all rehospitalizations and ipsilateral and contralateral limb events, including amputations, graft revisions, or graft occlusions. A graft that underwent reintervention or developed an occlusion was removed from the research component of the ultrasound follow-up studies.

Calculations 

Calculations for wall stiffness were based on modifications of the Moens-Korteweg formula (Eq 1),15 relating the elastic modulus of the vein graft to overall stiffness.

(1)
(2)
(3)
Where E is elastic modulus, ρ is density of blood (1.050 g/cm3), re is external radius, and ri is internal radius. The product of the elastic modulus and the thickness of the vein represents the overall stiffness and is equal to the quantity, 2ρri(PWV)2, (eq. 3).

The resolution of the ultrasound scanner is suboptimal for reproducible measurement of early thickness changes in a significant percentage of vein grafts. However, wall stiffness may be measured in the absence of thickness data and can be thought of as the force needed per unit length divided by the resultant strain.

Volumetric flow, Q, was calculated from commercially available software, Medical Imaging Analysis 5.0 software package (Iowa City, Iowa), by integrating the area under the velocity spectral waveform and dividing by the time to arrive at a time-averaged velocity. Mean flow was calculated by multiplying the time-averaged velocity by the mean area of the lumen (as obtained from the index segment M-mode measurements).

Mean shear stress was calculated according to the Hagen-Poiseuille formula (τw = 4μQ/πri3) where τw is shear stress in dynes/cm2, and mean volumetric flow is Q. The viscosity of blood, μ, is assumed to be 0.035 poise. Lumen radius, ri, is in centimeters.

Statistical methods 

All values are represented as mean ± SEM. Comparisons of measures between individual time points between groups were made with the unpaired t test. A repeated-measures analysis of variance (ANOVA) with autoregressive covariance structure of period 1 was used to compare trends in individual variables over time. Correlations were made with a standard linear regression, and the P value of the correlation and the r value are reported.

The primary clinical end point examined was the loss of primary patency (graft revision or occlusion). Graft patency was calculated by the life-table method with standard errors calculated by the Greenwood method. Comparison of event rates between groups was made with the log-rank test and Wilcoxon rank sum. The P value is reported with a significance level of .05.

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Results 

Patient characteristics 

This study evaluated 96 bypass grafts from 92 subjects (Table I), of which 60 (62.5%) were placed in men. Forty grafts (41.7%) were performed in patients with coronary artery disease, 56 (58.3%) in patients with diabetes mellitus, 54 (56.3%) in patients with hypertension, and 14 (14.6%) in patients with end-stage renal disease. Fifty-two (54.2%) of our subjects were current or former users of tobacco. The indications for bypass in this study (Table II) were claudication (30.2%), rest pain (15%), tissue loss (47.9%), and popliteal artery aneurysm (6.3%).

Table I. Demographics and risk factor profile of patients comprising the study population
Patients (n = 92)⁎ (%)
Age67
Male60(62.5)
Coronary artery disease40(41.7)
Diabetes mellitus56(58.3)
Hypertension54(56.3)
Dialysis14(14.6)
Hyperlipidemia60(62.5)
Smoking52(54.2)

⁎ 96 limbs.

Table II. Indications and characteristics of the bypass grafts under study
Indicationn%Typen%
Claudication2930.2Nonreversed GSV43−44.80
Rest rain1515.6Reversed GSV16−16.70
Ulceration3233.3In Situ GSV17−17.70
Gangrene1414.6Composite GSV6−6.30
Popliteal aneurysm66.3Arm vein5−5.20
Composite arm vein9−9.40
Inflow Outflow
CFA6466.7Popliteal36−37.50
SFA1919.8Tibial46−47.90
Popliteal1313.5Pedal14−14.60

GSV, great saphenous vein; CFA, common femoral artery; SFA, superficial femoral artery.

Bypass configurations and anastomotic sites are summarized in Table II. The conduits included nonreversed GSV in 43 (44.8%), reversed GSV in 16 (16.7%), in situ in 17 (17.7%), and composite GSV in 6 (6.3%). Arm vein was used in 14 patients as either a single segment (9.4%) or composite (5.2%) configuration.

Changes in index segment lumen diameter, and the relationship to initial shear stress 

Mean index segment lumen diameter of the entire cohort increased from 0.37 ± .01 cm to 0.45 ± 0.02 cm from the time of surgery to 6 months (P = .002, ANOVA; Fig 1, A), representing a 21.6% mean lumen diameter gain (median 14%, range −31% to +67%). An increase in lumen diameter occurred in 72% of the vein graft index segments (ie, positively remodeled), and 28% decreased in size (negatively remodeled). Thus, a significant variability in lumen diameter change was noted amongst the overall population, particularly within the first month (Fig 1, B). Most (74%) of the 6-month lumen gain occurred within the first month after implantation.

  • View full-size image.
  • Fig 1. 

    A, Mean index segment lumen diameter changes of the entire population, demonstrating early outward remodeling most pronounced between 0 and 1 month, P = .002. B, Scatter plot demonstrating mean and range of remodeling of graft configurations composed of greater saphenous veins in the 0-1 month and 1-3 month time interval. Data shown are for individual grafts with measurements at both of the indicated time points. All values are presented as mean ± SEM.

The lumen size of vein grafts composed of GSV tended to stabilize at 1 month, with no significant change in diameter occurring thereafter. In contrast, arm vein segments demonstrated a continued tendency for dilation throughout the 6-month study period. There was a significant difference in the final 6-month diameter of the index segments consisting of arm vein vs greater saphenous vein (0.61 cm vs 0.41 cm, P < .0001, unpaired t test; Fig 2). There was a weak negative correlation between the percentage of lumen change during the first month and starting vein diameter (r = .35; P = .01).

  • View full-size image.
  • Fig 2. 

    Great saphenous vein and arm vein index segments remodel in a similar fashion during the first month after bypass grafting. However, they diverge markedly between 1 and 6 months, P < .001. All values are presented as the mean index segment lumen diameter ± SEM.

Volume flow measurements were available from 26 patients, allowing for calculations of shear stress. Time-averaged volume flow increased during the study period from an intraoperative value of 161.1 ± 21.7 cm3/min to 302.2 ± 47 cm3/min at 6 months (P = .002). No correlation was found between initial mean flow rates and the change in diameter of the vein graft from 0 to 1 month (P = .6). The mean intraoperative index segment shear stress for this group was 25.4 ± 4.3 dynes/cm2. This value decreased to 18.6 ± 2.2 dynes/cm2 by 6 months (P = .41). Initial (intraoperative) graft shear stress was positively correlated with the change in index segment lumen diameter during the time interval between surgery and 1 month (r = .54, P = .03; Fig 3).

Pulse wave velocity and wall stiffness 

Vein graft PWV tended to increase over time, from 17.2 ± 1.16 m/s at surgery to 23.2 ± 2.4 m/s at 6 months (P = .008, ANOVA). The changes in wall stiffness (E × h) paralleled PWV and increased from 2.0 ± 0.6 Mdynes/cm at surgery to 3.3 ± 0.8 Mdynes/cm at 6 months (P = .01, ANOVA). This represents a 65% increase in the overall stiffness of the vein graft wall during the first 6 months after implantation. Stiffness did not change significantly during the initial month after surgery. The largest relative change in wall stiffness occurred in the interval from 1 month to 3 months, where the stiffness increased from 1.8 ± 0.3 Mdynes/cm to 3.3 ± 0.8 Mdynes/cm (Fig 4).

  • View full-size image.
  • Fig 4. 

    The overall population of grafts showed an increase in wall stiffness (P = .014) during the first 6 months after bypass graft, with the major change observed between 1 and 3 months. Graphed values are presented as the mean ± SEM.

Clinical outcomes 

During the course of the study, 24 subjects experienced either graft occlusion (n = 5) or revision (n = 19) during a mean follow-up period of 904 days (range, 13 to 2668). No correlation was found between graft events and initial vein graft diameter at the time of implantation. Further, the reintervention and occlusion rate among the different groups of grafts did not differ in situ statistically (P = .22, χ2). Specifically, there were 10 (23.3%) of 43 in the nonreversed GSV, 6 (37.5%) of 16 in the reversed GSV, 2 (11.7%) of 17 in the in situ GSV, 3 (50%) of 6 in the composite GSV, 0 (0%) in the 5 single-segment arm veins, and 3 (33.3%) of 9 in the composite arm veins.

In this study, vein grafts that remained primarily patent demonstrated a trend of increased index segment lumen diameter during the first month after implantation compared with those that subsequently failed (21% mean diameter increase for patent grafts vs 4% diameter increase for those with subsequent events, P = .12). Looked at another way, vein bypass grafts that demonstrated early positive remodeling (ie, positive change in index segment lumen diameter between 0 and 1 month) had a trend toward improved primary patency (P = .08, log rank test) compared to grafts with early negative remodeling. We also observed a trend toward greater wall stiffness at 1 month (2.7 vs 1.5 Mdynes, P = .08) in the grafts that went on to subsequent revision or occlusion vs those that remained patent.

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Discussion 

These data indicate that lower extremity vein bypass grafts undergo two distinct phases of early remodeling. In most groups, an initial period of outward remodeling occurs, primarily within the first month of implantation, which is followed by the development of increasing wall stiffness in the ensuing months. Most of the lumen gain in GSV reconstructions occurs within the first month and is followed by a period of stabilization, which indicates that the lumen of functioning grafts is generally preserved during the most proliferative period.5

A notable exception to this early remodeling pattern was seen in the subset of arm vein conduits, which in this study demonstrated a tendency toward dilation over the first 6 months. Of note, we did not observe aneurysmal formation in the arm vein conduits. From these observations, we hypothesize that early outward remodeling is a normal physiologic adaptive response of the arterialized venous conduit and, in fact, may be critical for long-term, revision-free patency of the bypass graft.

In this study, initial shear stress was correlated with the change in index segment lumen diameter over the first postoperative month. This suggests that the ability of the vein to undergo early positive remodeling may be a shear-dependent process, consistent with prior experimental evidence.3, 5, 6, 7

Zwolak et al5 proposed and provided experimental evidence for a mechanism by which lumen dilatation occurs to normalize the shear stress to a preset mean value. In a rabbit vein graft model, these investigators noted that the lumen radius increased 64% over the 24-week study period.5 Fillinger et al6 expanded this idea to human subjects by performing serial duplex evaluation on 48 human in situ lower extremity bypass grafts. Using a regression model, they were able to determine that change in lumen diameter correlated with initial lumen diameter and initial shear stress. An important difference between their report and ours is that our initial measurements were made intraoperatively, whereas their initial measurements were made 1 week after bypass. Nevertheless, we also were able to confirm that veins were able to successfully remodel so that shear stress was restored to a more physiologic range over time.5, 6

Factors other than hemodynamics, perhaps related to structural, cellular, or molecular properties of the conduit may also regulate remodeling. Upchurch et al,16 in a case-control study comparing peripheral vascular reconstructions for popliteal aneurysmal disease with controls with occlusive disease noted that vein grafts performed for aneurysmal disease dilated to a greater extent then the controls. These authors speculated that the differential dilation of the veins was due to an intrinsic property of its wall, such as matrix composition and metalloproteinase activity.16 Further studies are needed in this area.

Our data also suggest that early outward remodeling of the graft may be a favorable marker for subsequent patency. Conversely, grafts that remodel negatively in the first month displayed a trend towards more revisions or occlusions. Whether remodeling failure represents an intrinsic property of the vein wall that does not allow for early dilatation or reflects unfavorable hemodynamic circumstances (ie, low shear stress) is not determined by our data It is interesting, however, to also note that at 1month, there was a trend in the veins that subsequently failed to be stiffer then those that did not (P = .08). This suggests that graft failure may be linked to an altered biomechanical response in the graft wall.

The Moens-Korteweg equation relates PWV to wall stiffness. The PWV is currently one of the most accurate noninvasive measurements of conduit stiffness.17 The assumptions underlying the Moens-Korteweg equation are that the tube has a thin wall (ie, h/2ri is small) of uniform caliber and contains an ideal incompressible liquid. The PWV is measured as the distance between two recording sites in the line of pulse travel (length of a vein graft) divided by the difference in time delays of the upstroke of a pressure or flow waves at the two sites (distance/transit time).

The PWV has been used extensively in clinical practice and also as an end point in clinical trials.18 For example, an accelerated common carotid–femoral artery PWV has been shown to be an independent predictor of all-cause and cardiovascular mortality in hypertensive patients,18 in patients with end-stage renal disease,19 and elderly subjects.20 Arterial stiffness has been shown to be associated with inflammation and elevated C-reactive protein.21, 22 This suggests that stiffening of conduits is an active process rather than a mere passive result of elevated blood pressure or the inevitable consequence of aging.

Regardless of the mechanism, however, the stiffening of the vein graft’s wall must be due to either a change in wall mass or the elastic modulus of its component structures. Animal models,5, 7, 23, 24 human histologic studies, and ex vivo experiments25, 26 have documented thickening of the wall in response to arterial hemodynamics. In an earlier study where we were able to measure wall thickness in a smaller cohort of grafts, we found that the elastic modulus increased to a much greater extent then could be accounted for by thickness alone.13 Thus we speculate that in addition to increased thickness, changes in wall composition (such as increased collagen) may account for the dramatic increase in wall stiffness during the initial 3-month interval after bypass.27

Techniques used in this investigation have important limitations. Limitations of the PWV approach to characterize vessel stiffness have been described.13, 28 Briefly, the measurement is an integrated value for stiffness over the entire vein graft and fails to account for the considerable local variability within the grafts. Veins have distinct morphologic variation in caliber, tapering, intimal hyperplasia, and smooth muscle hypertrophy that accounts for local wall stiffness and viscoelastic properties that predisposes them to stenosis and failure.4, 29, 30 It is possible that other noninvasive technologies such as tonometry or elastography31 may allow for the creation of a more detailed map of local wall properties. Variations in heart rate and blood pressure can significantly affect the PWV.S28

Finally, the pixel resolution prohibited the discrimination of time delays <0.5 milliseconds and there are inherent limitations of the image analysis software. Thus, shorter grafts that have shorter QRS-flow onset time delays will have a larger relative error. Our error estimation suggest that grafts that are <30 cm cannot be reliably measured, since the potential error exceeds the variance among subjects.32 Commercially available imaging analysis software packages with the ability to analyze raw radio-frequency data and also perform simultaneous (instead of sequential) measurements at both the proximal and distal ends of the graft would improve the PWV accuracy.

Another significant limitation to the study is the variability in the number of observations at each time points. A repeated-measures ANOVA, such as used in this analysis, can overcome this limitation to some extent. Graphically, however, there are no significant differences in the temporal trends of diameter and stiffness if only subjects who have observations at all time points are included.

Finally, no reliable noninvasive method is currently available to measure vein graft wall thickness and, thereby, wall stress. In our previous efforts using M-mode ultrasonography, we were able to determine wall thickness in only 66% of subjects.13 These dimensions are on the order of 0.5 mm, and changes over the ensuing 6 months are in the range of ≤.3 mm.13 In addition to lumen resolution, a major limitation in assessing wall thickness is the lack of echo-differentiation between the vein graft adventitia and the surrounding stroma in which it is embedded. We are currently investigating other modalities, such as magnetic resonance imaging and intravascular ultrasonography, to better characterize wall thickness changes over time in vein grafts.33, 34, 35

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Conclusion 

Vein grafts placed within the arterial circulation undergo a series of early structural and ultrastructural events that eventually culminate in measurable morphometric changes of the conduit. Our observations suggest that arterialized veins remodel themselves significantly and rapidly (≤3 months) and these early remodeling patterns may have a direct impact on the overall clinical outcome of lower extremity reconstructions.

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Author contributions 

Conception and design: CO, JJ, MG, MB, MAC, MSC

Analysis and interpretation: CO, NW, JJ, MG, MB, PG, MAC, MSC

Data collection: CO, NW, JJ, MG, MSC

Writing the article: CO, MSC

Critical revision of the article: CO, NW, JJ, MG, MB, PG, MAC, MSC

Final approval of the article: CO, NW, JJ, MG, MB, PG, MAC, MSC

Statistical analysis: CO, PG, MSC

Obtained funding: CO, MAC, MSC

Overall responsibility: CO, MSC

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 Supported by funding from the National Heart, Lung, and Blood Institute (HL75771 to M. A. C. and M. S. C.), and by the Clinical Investigator Training Program in Health, Science, and Technology, Harvard Medical School and Massachusetts Institute of Technology (C. D. O.).Competition of interest: none.

PII: S0741-5214(06)01024-X

doi:10.1016/j.jvs.2006.06.005

Journal of Vascular Surgery
Volume 44, Issue 4 , Pages 740-746, October 2006

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