The Impact of Clinical Follow-Up After Revascularization on the Outcomes of Patients with Chronic Limb Threatening Ischemia.

BACKGROUND: Guidelines for optimal follow-up for patients undergoing lower extremity revascularization (LER) for peripheral arterial disease recommend multiple visits with imaging during the first year followed by yearly monitoring thereafter. Critical limb-threatening ischemia (CLTI) patients are at a greater risk for mortality and limb amputation than claudicants and thus necessitate closer monitoring. The goal of this article is to study the effects of compliance with follow-up after revascularization for patients with CLTI on major amputation rates and mortality. METHODS: A single-center retrospective chart review of consecutive patients undergoing LER for CLTI was performed. Patients were stratified based on compliance with follow-up to compliant or noncompliant cohorts. Patient characteristics, reinterventions, and perioperative and long-term outcomes were compared between the 2 groups. RESULTS: There were 356 patients undergoing LER and 61% (N = 218) were compliant. There was no significant difference in baseline characteristics between the 2 groups. Noncompliant patients were more likely to undergo endovascular interventions compared to compliant patients (92.8% vs. 79.4%, P = 0.03). There was no difference in perioperative outcomes between the 2 groups with overall 30-day mortality of 0.6%. After mean follow-up of 2.7 years, compliant patients had greater ipsilateral reintervention rates (49.1% vs. 34.1%, P = 0.005) and overall reintervention rates (61% vs. 44.2%, P = 0.002) compared to noncompliant patients. There was no significant difference in mortality or ipsilateral major amputations between the 2 groups. CONCLUSIONS: Patients who were compliant with follow-up after LER for CLTI underwent more reinterventions with no difference in mortality or major limb amputation. Further research regarding the threshold for reintervention and the optimal schedule for follow-up in patients with CLTI is needed.

Reinterventions in Patients with Claudication and Chronic Limb Threatening Ischemia.

BACKGROUND: Patients with peripheral artery disease (PAD) present with claudication or chronic limb threatening ischemia (CLTI). CLTI patients have a more advanced stage of atherosclerosis and increased comorbidities compared to claudicants, and are at an elevated risk of major amputation and mortality after lower extremity revascularization (LER). However, the frequency of reinterventions for claudication and CLTI have not been compared. Our hypothesis is that patients with CLTI undergo more frequent reinterventions to prevent major amputation. METHODS: A single-center retrospective chart review of consecutive patients undergoing lower extremity revascularization (LER) for PAD in 2013-2015 was performed. Patients were stratified based on indication for revascularization into claudication or CLTI. Patient characteristics, outcomes, and reinterventions were compared between the 2 groups. RESULTS: There were 826 patients undergoing LER and 44% (N = 361) had CLTI. Patients treated for CLTI were more likely to be smokers (P < 0.001), to have diabetes (P< 0.001), chronic renal insufficiency (P< 0.001), end stage renal disease (P< 0.001), and cardiac disease (P< 0.001). CLTI patients were less likely to be on optimal medical management as reflected by decreased rate of aspirin (P< 0.001), ADP receptor/P2Y12 inhibitors (P< 0.001), and statins (P< 0.001) compared to patients with claudication. Patients with CLTI had significantly higher major amputation (3.7% vs. 0.2%, P< 0.001) and mortality (1.4% vs. 0.2%, P = 0.092) at 30 days. At long-term follow up, patients with CLTI had higher rates of major amputation (15.5% vs. 1.3%, P < 0.001) and mortality (37.1% vs. 18.1%, P < 0.001) compared to patients with claudication. There was a significant difference in mean follow-up time between the 2 cohorts (claudication: 3.7 ± 1.5 years versus CLTI: 2.6 ± 1.8 years, P < 0.001). There was no significant difference in the ipsilateral reintervention rate between the 2 groups (claudication: 39.6% vs. CLTI: 42.7%, P = 0.37) or the mean number of ipsilateral reinterventions (claudication: 2.0 ± 1.6 vs. CLTI: 2.0 ± 1.7). However, after adjusting for follow-up time, the mean number of reinterventions per year was significantly higher for CLTI patients compared to patients with claudication (1.4 ± 2.2 vs. .6 ± 0.7 intervention per year, P < 0.001). CONCLUSIONS: Patients undergoing LER for CLTI undergo more frequent reinterventions over time compared to patients treated for claudication. Research on reinterventions after LER should include reporting of the frequency of reintervention adjusted for the follow up period in addition to the reintervention rate defined as the percentage of patients undergoing reintervention.

PD-L1 (Programmed Death Ligand 1) Regulates T-Cell Differentiation to Control Adaptive Venous Remodeling.

OBJECTIVE: Patients with end-stage renal disease depend on hemodialysis for survival. Although arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, the primary success rate of AVF is only 30% to 50% within 6 months, showing an urgent need for improvement. PD-L1 (programmed death ligand 1) is a ligand that regulates T-cell activity. Since T cells have an important role during AVF maturation, we hypothesized that PD-L1 regulates T cells to control venous remodeling that occurs during AVF maturation. Approach and results: In the mouse aortocaval fistula model, anti-PD-L1 antibody (200 mg, 3×/wk intraperitoneal) was given to inhibit PD-L1 activity during AVF maturation. Inhibition of PD-L1 increased T-helper type 1 cells and T-helper type 2 cells but reduced regulatory T cells to increase M1-type macrophages and reduce M2-type macrophages; these changes were associated with reduced vascular wall thickening and reduced AVF patency. Inhibition of PD-L1 also inhibited smooth muscle cell proliferation and increased endothelial dysfunction. The effects of anti-PD-L1 antibody on adaptive venous remodeling were diminished in nude mice; however, they were restored after T-cell transfer into nude mice, indicating the effects of anti-PD-L1 antibody on venous remodeling were dependent on T cells. CONCLUSIONS: Regulation of PD-L1 activity may be a potential therapeutic target for clinical translation to improve AVF maturation.

Inhibition of T-Cells by Cyclosporine A Reduces Macrophage Accumulation to Regulate Venous Adaptive Remodeling and Increase Arteriovenous Fistula Maturation.

OBJECTIVE: Arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, but the primary success rate of AVF remains poor. Successful AVF maturation requires vascular wall thickening and outward remodeling. A key factor determining successful AVF maturation is inflammation that is characterized by accumulation of both T-cells and macrophages. We have previously shown that anti-inflammatory (M2) macrophages are critically important for vascular wall thickening during venous remodeling; therefore, regulation of macrophage accumulation may be an important mechanism promoting AVF maturation. Since CD4+ T-cells such as T-helper type 1 cells, T-helper type 2 cells, and regulatory T-cells can induce macrophage migration, proliferation, and polarization, we hypothesized that CD4+ T-cells regulate macrophage accumulation to promote AVF maturation. Approach and Results: In a mouse aortocaval fistula model, T-cells temporally precede macrophages in the remodeling AVF wall. CsA (cyclosporine A; 5 mg/kg, sq, daily) or vehicle (5% dimethyl sulfoxide) was administered to inhibit T-cell function during venous remodeling. CsA reduced the numbers of T-helper type 1 cells, T-helper type 2, and regulatory T-cells, as well as M1- and M2-macrophage accumulation in the wall of the remodeling fistula; these effects were associated with reduced vascular wall thickening and increased outward remodeling in wild-type mice. However, these effects were eliminated in nude mice, showing that the effects of CsA on macrophage accumulation and adaptive venous remodeling are T-cell-dependent. CONCLUSIONS: T-cells regulate macrophage accumulation in the maturing venous wall to control adaptive remodeling. Regulation of T-cells during AVF maturation may be a strategy that can improve AVF maturation. Graphic Abstract: A graphic abstract is available for this article.

Outcomes of treatment with paclitaxel-coated devices for peripheral arterial disease.

OBJECTIVE: The treatment of femoropopliteal peripheral artery disease (PAD) using paclitaxel-coated devices (PCDs) has been shown to improve patency in several randomized trials. However, a recent meta-analysis of trial data suggested an increased risk of mortality with PCD usage. Although subsequent studies have found no association with mortality, the subject has remained controversial. Thus, the aim of the present study was to further investigate the outcomes and causes of mortality for patients treated with PCDs. METHODS: Patients who had undergone endovascular interventions for PAD from 2013 to 2016 at a single institution were reviewed. The patients were stratified by the use of PCDs, which included drug-coated balloons and drug-eluting stents. The cumulative dose of paclitaxel was calculated for the patients who had received multiple interventions. The causes of mortality were identified and compared between the two groups. RESULTS: Of the 366 included patients, 138 (38%) had received a PCD and 228 (62%) had received a non-drug-coated (NDC) device. Patients treated with PCDs were less likely to have undergone open surgery compared with patients treated with NDC devices. No differences were found in the indications or 30-day outcomes between the two groups. After a mean follow-up of 3.1 ± 1.8 years, no differences were found in the primary patency, reintervention rate, mean number of reinterventions, major amputation (5% vs 4%; P = .465), or mortality (16% vs 20%; P = .363) between the PCD and NDC groups. Also, no overall difference was found in the cause of mortality with and without PCD use or in the Kaplan-Meier survival curves. Furthermore, PCD use was not associated with an increased risk of mortality in Cox regression analysis. The cumulative dose of paclitaxel in patients treated with PCDs ranged from 383 to 49,259 µg (median, 7561 µg). A comparison of the patients treated with a cumulative dose of paclitaxel in the upper 50th percentile compared with the lower 50th percentile showed no significant differences in mortality (13% vs 19%; P = .333). CONCLUSIONS: PCD use was shown to be safe and not associated with an increased risk of long-term mortality in the present study. Continued monitoring of PCD use is warranted to ensure the safety of this technology.

Multiple Reinterventions for Claudication are Associated with Progression to Chronic Limb-Threatening Ischemia.

BACKGROUND: Claudication has a relatively benign natural history, associated with a low risk of limb loss. However, rates of progression to chronic limb-threatening ischemia (CLTI) following lower extremity revascularization (LER) for claudication remain unclear. This study examines the long-term outcomes and risk factors associated with progression to CLTI after LER for claudication. METHODS: A single-center retrospective review of patients undergoing LER for claudication was performed from 2013-2016. Patients were stratified based on whether they progressed to CLTI or not. RESULTS: There were 448 patients (502 limbs) treated for claudication, and 57 (12.7%) progressed to CLTI with a mean follow up time of 3.7 ± 1.5 years. Among patients who progressed, 23 (5.1%) developed tissue loss, 34 (7.6%) developed rest pain, and 6 (1.2%) underwent major amputation. The mean time of progression to CLTI was 1.6 ± 1.5 years after index LER. Patients who progressed to CLTI were more likely to have a history of congestive heart failure and prior open revascularizations compared with those who did not progress. There was no difference in type or level of index revascularization between the two groups and no difference in perioperative complications. Patients who developed CLTI had significantly higher rates of reinterventions and a mean number of reinterventions after index LER prior to developing CLTI compared to those who did not progress. Multivariable logistic regression demonstrated that history of congestive heart failure (OR = 2.8 [1.2-6.6]), stroke (OR = 2.6 [1.1-6.1]), prior open procedure (OR = 2.8 [1.3-5.9]) and increasing number of reinterventions after index LER (OR = 2.9 [1.5-5.7]) were independently associated with disease progression to CLTI. CONCLUSIONS: Multiple reinterventions and previous open revascularization are associated with progression to CLTI following LER for claudication. Patients with atherosclerosis in the coronary and cerebrovascular beds are also more likely to have a progression of claudication to CLTI after LER.

Distinct subsets of T cells and macrophages impact venous remodeling during arteriovenous fistula maturation.

Patients with end-stage renal failure depend on hemodialysis indefinitely without renal transplantation, requiring a long-term patent vascular access. While the arteriovenous fistula (AVF) remains the preferred vascular access for hemodialysis because of its longer patency and fewer complications compared with other vascular accesses, the primary patency of AVF is only 50-60%, presenting a clinical need for improvement. AVF mature by developing a thickened vascular wall and increased diameter to adapt to arterial blood pressure and flow volume. Inflammation plays a critical role during vascular remodeling and fistula maturation; increased shear stress triggers infiltration of T-cells and macrophages that initiate inflammation, with involvement of several different subsets of T-cells and macrophages. We review the literature describing distinct roles of the various subsets of T-cells and macrophages during vascular remodeling. Immunosuppression with sirolimus or prednisolone reduces neointimal hyperplasia during AVF maturation, suggesting novel approaches to enhance vascular remodeling. However, M2 macrophages and CD4+ T-cells play essential roles during AVF maturation, suggesting that total immunosuppression may suppress adaptive vascular remodeling. Therefore it is likely that regulation of inflammation during fistula maturation will require a balanced approach to coordinate the various inflammatory cell subsets. Advances in immunosuppressive drug development and delivery systems may allow for more targeted regulation of inflammation to improve vascular remodeling and enhance AVF maturation.