The Effect of Lower Limb Revascularization on Flow, Perfusion, and Systemic Endothelial Function

Introduction

Peripheral arterial disease (PAD) is a chronic atherosclerotic process that causes narrowing or occlusion of peripheral arteries, particularly in the lower limbs. 1 Although the majority of patients remain asymptomatic, symptomatic progression often manifests as intermittent claudication (IC) or, in severe cases, chronic limb-threatening ischemia (CLTI). 2 Chronic limb-threatening ischemia is associated with a particularly poor prognosis, with an estimated annual amputation and mortality rate of 12% and 25%, respectively. 3 Much of the associated mortality risk associated with PAD is attributable to the increased risk of myocardial infarction and stroke, for which PAD is an independent risk factor. 4^,5

The management for PAD is multimodal. Conservative treatment centers around the optimization of cardiovascular (CV) risk factors. Patients with short distance claudication or CLTI are offered open or endovascular revascularization, with the aim of improving blood flow and tissue perfusion, in order to prevent limb loss and improve symptomatology. Observational studies have demonstrated higher healing rates in patients with CLTI and tissue loss undergoing revascularization as compared with those undergoing conservative management. 6 Additionally, PAD is associated with systemic endothelial dysfunction and inflammation, which can accelerate existing CV disease. 7 ^–10 This is thought to be the result of reduced vessel wall shear stress and repeated ischemia–reperfusion injury. 11 Therefore, it is postulated that achieving improvements in flow and perfusion with revascularization may improve systemic endothelial function and also lead to a wider protective effect to the CV system. 8

Flow, perfusion, and systemic endothelial function may well be closely related. However, this is a relatively recent concept with little evidence supporting it. In order to effectively investigate this association in future studies, we must first better understand the effect of revascularization on each of these parameters. Therefore, the aim of this systematic review is to explore the impact of revascularization on (1) lower limb blood flow, (2) tissue perfusion, and (3) systemic endothelial function.

Methods

Results

Our initial search identified 4642 papers. Of these, 63 publications were selected for full-text review based on their title and abstract (Figure 1). A full-text screening resulted in the final selection of 19 studies; 13 of these studies reported the effect of revascularization on flow (Table 1), 9 articles reported tissue perfusion measurements (Table 2), and 5 articles reported on systemic endothelial function (Table 3). Key findings are presented in Figure 2.

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Description of Studies

Only 1 study was a randomized controlled trial. 11 Of the remaining studies, 15 were prospective and 3 were retrospective. Sample sizes ranged from 9 to 85, with a total number of 707 participants across all studies. A total of 697 limbs underwent endovascular or open bypass revascularization, and 86 participants participated as controls in 5 studies (angiography [n = 31], exercise treatment [n = 16], best medical therapy [n = 20], and healthy volunteers [n = 12]). A total of 261 patients with IC and 375 patients with CLTI were included across the studies. A total of 316 (43.8%) patients had diabetes mellitus (DM) and 4 studies recruited only patients with DM. Studies that included patients with DM and non-DM reported separate results for each group. Mean age of patients in the included studies ranged between 47 and 94 years, with 65% men and 36% women. Study duration ranged from 14 days to 48 months.

Studies Assessing Flow

Thirteen studies reported ankle brachial pressure indices (ABPIs) after revascularization. 11^,20^,23^,24^,13^,22^,18^,21^,17^,31 Nine of these studies reported significant improvement in initial ABPI. 20^,22^,18^,21^,17^,12^,14^,16^,19 Overall, success in improving flow was lower in patients with CLTI compared to patients with IC at 1 to 12 months follow-up; Savolainen et al 16 performed revascularization on 55 cases (26 CLTI and 21 IC) and reported a better outcome in patients with IC compared to patients with CLTI. Alback et al 19 reported 83% and 66% rate of hemodynamic success at 1-month follow-up in patients with IC and CLTI, respectively.

A randomized controlled trial compared percutaneous transluminal angioplasty (PTA) with best medical treatment in 17 patients with IC and reported significant increase in ABPI in the PTA group only (0.63-1.05; P = .0004). 15

Borozan et al 23 observed a 72% initial ABPI improvement in 34% of patients with IC treated with PTA, followed by a significant deterioration of flow during the follow-up period. Continued hemodynamic success was maintained in 37%, and overall long-term success was 27% during a mean follow-up of 16 months. The average time to deterioration in ABPI following PTA was 14 months.

Flanigan et al 24 observed an immediate improvement in ABPI in only 62% of patients with IC treated with PTA, despite achieving 93% immediate anatomical success. Only 48% of patients maintained hemodynamic success during a mean follow-up duration of 9 months.

Pawlaczyk and colleagues 13 measured flow in 3 groups of patients: bypass (group 1, n = 30), PTA (group 2, n = 29), exercise only (group 3, n = 20). They reported a significant improvement in mean ABPI in groups 1 and 2 at 90 days postprocedure (mean ABPI: 0.57 and 0.59 in groups 1 and 2, respectively, improved to 0.75 in both groups; P < .049). No change in ABPI values was observed in the exercise group (group 3).

Studies Assessing Tissue Perfusion

We identified 8 studies that measured changes in perfusion after PTA and bypass in 162 patients (CLTI, n = 122; IC, n = 40; DM, n = 85) using 3 different methods (laser Doppler method, transcutaneous pressure of oxygen [TcPO₂], and heat washout technique). 22^,18^,21^,17^,12^,26^,25^,27 All 8 studies observed an improvement in perfusion when compared with preintervention measurements, regardless of the method of perfusion assessment. Kim et al 25 reported an increase in mean TcPO₂ from 12.7 ± 8.9 to 43.6 ± 24.1 mm Hg (P < .01) at 1 week post-PTA. Jacobs et al 21 reported an increase in mean TcPO₂ from 36 ± 14 to 59 ±16 mm Hg at rest. They also demonstrated an increase in TcPO₂ in reactive hyperemia from 19 ± 15 to 58 ± 32 mm Hg post-op (P < .001). 21 Osmundson et al 22 provided separate results following open revascularization for patients with DM and non-DM with CLTI. In the DM group, mean TcPO₂ in the horizontal position improved from 15 to 50 mm Hg and mean TcPO₂ with the leg elevated improved from 4 to 40 mm Hg. In the non-DM group, the corresponding values were 23 to 60 and 5 to 47 mm Hg.

Wagner et al 18 demonstrated that improvements in perfusion may take as long as 6 weeks to manifest following endovascular revascularization (mean TcPO₂: prior to revascularization 32 mm Hg, at completion 34 mm Hg, 37 mm Hg 1 day following revascularization, and 45 mm Hg 6 weeks following revascularization). Saucy et al 17 (n = 10) reported a significant increase in skin blood flow (SBF) on the treated side 10 days post-bypass (hindfoot from 148 ± 58 to 203 ± 83 perfusion units [PU] and forefoot from 135 ± 67 to 202 ± 86 PU, P = .001). Interestingly, they observed a statistically significant decrease in SBF on the untreated side at 10 days postoperation (hindfoot from 208 to 133 PU and the forefoot from 250 to 176 0.94 PU, P = .001). No decrease in flow was observed on the untreated side. The mechanism behind the decrease in SBF was not clear. However, the authors hypothesized that it may be due to a neuromediated vasoconstriction of microvascular networks. In this study, the authors reported a significant increase in flow as measured by toe pressures (P = .001) on the treated side and demonstrated a good correlation between SBF and toe pressure (ie, perfusion and flow).

Rother et al 12 measured microcirculatory changes (using laser Doppler tissue spectrometry) continuously during and immediately following tibial PTA in 30 patients with CLTI (20 diagnosed with DM) at different angiosome regions of the index foot and reported a statistically significant increase in microcirculation in all patients with overall mean oxygen saturation (sO₂) improvement of 62.4%. They also compared directly and indirectly revascularized angiosomes and found no difference between the 2 groups in either flow or sO₂ parameters postintervention. This suggests that changes in tissue perfusion following revascularization are global and not restricted to angiosome-defined borders.

Arora et al 26 compared the post-bypass vasodilatory response (using laser Doppler imaging to measure vasodilation of the foot skin in response to heat and to iontophoresis of 1% acetylcholine and 1% sodium nitroprusside) in 13 patients with diabetic neuropathy and CLTI (group DI) with 3 different groups of patients who did not undergo revascularization (diabetic neuropathy without CLTI [group DN, n = 15], no neuropathy or ischemia [group D, n = 7], and healthy individuals [group C, n = 12]). The response post-bypass was considerably improved when compared with baseline measurements (response to heat: 289% increased to 427%; response to acetylcholine: 6% increased to 26%, measured in volts P < .05). However, the post-bypass response was comparable with the CLTI without neuropathy group and it was still significantly lower (P < .0001) when compared with no neuropathy and healthy groups despite a successful revascularization.

Studies Assessing Systemic Endothelial Function

Overall, 5 (165 limbs) studies reported the impact of revascularization on systemic endothelial function. 15^,31^,13^,28 ^–30 Tsai et al 29 investigated the effect of bypass surgery on plasma endothelin (ET)-1 and nitric oxide (NO) concentrations, plasma soluble intercellular adhesion molecules (sICAMs), soluble vascular adhesion molecules (sVCAMs), C-reactive protein (CRP), lymphocyte CD11a/CD18, and neutrophil CD11b/CD18 before and at 1 and 7 days postsurgery in 21 diabetic patients. They found no significant change in any of these parameters.

Danielsson et al 30 investigated the effect of revascularization on white blood cell (WBC) and platelet count, expression of CD11b/CD18 on granulocytes and monocytes, and CD41 on platelets and soluble endothelial markers (sICAM-1 and VCAM-1, soluble E-selectin and soluble P-selectin) 4 weeks following bypass. They found a decrease in WBCs and granulocyte counts 4 weeks postrevascularization in the subgroup of patients with ulcers and gangrene. They also noted a decrease in the endothelial marker ICAM-1 and increase in VCAM-1. No significant changes were seen in patients with rest pain, but no tissue loss (n = 8).

Three studies measured FMD to evaluate the effect of revascularization on systemic endothelial function. Flow-mediated dilatation is the expression of the change in diameter of brachial artery after a period of arm ischemia, which indicates the endothelial response to shear stress. Pawlaczyk and colleagues 13 measured FMD in 3 groups of patients (n = 79) with severe IC: bypass (group 1), PTA (group 2), and exercise only (group 3). They reported a significant improvement in FMD in groups 1 and 2, 90 days postprocedure (mean FMD: 3.88%-6.69%, P < .01; and 4.27%-4.8%, P = .049, respectively). No change in FMD values was observed in the exercise group (group 3).

Unal et al reported significant increase in FMD values in 54 patients with IC 4 weeks post-bypass (9.2% ± 2.1% to 16.2% ± 4.5%; P < .01) as well as considerable decrease in serum concentrations of interleukin-6, tumor necrosis factor α, and CRP post-bypass (36.5 ± 8.2 mg/mL, 43.9 ± 8.8 nmol/L, 13.3 ± 1.6 mg/mL, and 13.5 ± 1.8 mg/L, respectively, P < .05). They also reported significant positive correlation between FMD and serum NO (r = 0.51; P = .0093). 28

A randomized controlled trial compared PTA with best medical treatment in 17 patients with IC and reported a significant increase in FMD (4.96%-6.44%; P = .02) and a statistically significant decrease in WBC (7.6-6.9 × 10⁶/mL; P = .03) at 4 weeks post-PTA revascularization. 15 No change was observed for CRP or fibrinogen. No change in these parameters was observed in the best medical treatment group.

Discussion

Currently, lower limb revascularization is performed to increase limb perfusion by improving flow. Peripheral arterial disease has also been strongly associated with systemic endothelial dysfunction and inflammation, 32^,33 but the effect of revascularization on these parameters remains unclear. This is the first systematic review to explore the effect of revascularization on flow, perfusion, and systemic endothelial dysfunction.

The results from the limited number of studies in this review suggest that improvement in perfusion following revascularization is comparable when considering patients with and without DM. 22 Patients with DM and neuropathy are at highest risk of microcirculatory dysfunction. 34 However, Arora et al 26 suggest that foot perfusion and response to heat and acetylcholine can be significantly improved with revascularization in patients with diabetic neuropathy, although the response appears to be inferior to that for patients without DM and those with DM without neuropathy.

Included studies suggest that the likelihood of improving flow is lower in patients with CLTI compared to those with IC. 21^,17 Reasons for this observation are likely multifactorial and may relate to the often multilevel and complex anatomy of disease in patients with CLTI and also the limitations in methods used to assess flow, such as the confounding effect of calcification on ABPI measurements. 35

When considering PTA, anatomical success may not always translate into hemodynamic success. Flanigan et al 24 reported a 93% anatomical success but only 62% hemodynamic success immediately post-PTA. Clearly defined flow or perfusion end points may better translate to clinical benefit, although this remains to be investigated. Importantly, as observed in a number of studies in this review, improvements in perfusion may take weeks to become apparent. 23 Studies measuring systemic endothelial dysfunction using FMD were typically performed at least 4 weeks following revascularization. When considering systemic endothelial dysfunction following bypass surgery, measurements in the first few weeks may also be confounded by inflammation related to the operation. Additionally, patients may require hemodynamic support following the procedure, which may further confound measurements of flow, perfusion, and systemic endothelial dysfunction. This may offer an explanation for the conflicting results regarding the effect of revascularization on biochemical markers of systemic endothelial dysfunction. Although a number of studies found significant reductions in biochemical markers, 15^,28^,30 Tsai et al 29 only performed measurements 7 days following bypass surgery and did not observe such changes.

The magnitude of improvements in ABPI and FMD following revascularization seems to be equivocal for bypass and PTA. 13 However, there is paucity of long-term follow-up data regarding the effect of revascularization on flow, perfusion, and systemic endothelial dysfunction. The limited available evidence suggests that deterioration in flow parameters such as ABPI is common even in claudicants, with an average time to deterioration of approximately 14 months after revascularization. 23^,24

Although one study assessed the correlation between flow and perfusion, 13 none of the studies directly assessed the association between flow or perfusion with systemic endothelial dysfunction. Pawlaczyk et al and Husmann and colleagues did demonstrate improvements in flow and FMD but did not assess the correlation between them. 13^,15

One study suggested that improvements in systemic endothelial dysfunction measured with FMD are only observed in those with tissue loss. 30 However, other studies, assessing systemic endothelial dysfunction in patients with IC and CLTI, with and without tissue loss, noted improvements when measurements were taken a few weeks following revascularization. 31^,13 There are a number of mechanisms that may be contributing to improvements in systemic endothelial function, including healing ulcers, increase in shear stress, and a reduction in inflammation secondary to a decrease in ischemia–reperfusion injury. 15 However, studies included in this review do not adequately investigate this hypothesis. Importantly, they lack direct measures of flow (eg, Duplex ultrasound and strain gauge plethysmography) and local endothelial function proximal and distal to the site of revascularization. Future studies should address these limitations in order to further our understanding of the association between flow, perfusion, and systemic endothelial function.

Limitations

There is a paucity of recent evidence on this topic as most studies were conducted over a decade ago. Studies were also limited by small sample size, short follow-up period, and significant heterogeneity in methodology including inclusion criteria, revascularization approach, outcome metrics, and measurement technique. The latter is particularly relevant to the assessment of FMD, which can only be reliably measured if standard protocols are followed. The included studies did not report FMD methodology in sufficient detail or reference up-to-date FMD assessment guidelines. 36 Additionally, none of the studies controlled for optimization of medical therapy such as initiation of statin therapy or level of physical activity, which may change postrevascularization due to improved IC and influence flow, perfusion, and systemic endothelial function measurements. Furthermore, none of the included studies provided a meaningful assessment of the association between flow, perfusion, and systemic endothelial function following revascularization.

Conclusion

Current evidence suggests that revascularization has a positive effect on flow, perfusion, and systemic endothelial dysfunction. There is a need for well-designed studies to explore the association between flow, perfusion, and systemic endothelial dysfunction.