Ryan McEnaney

Predictors of failure and success of tibial interventions for critical limb ischemia

OBJECTIVE The efficacy of tibial artery endovascular intervention (TAEI) for critical limb ischemia (CLI) and particularly for wound healing is not fully defined. The purpose of this study is to determine predictors of failure and success for TAEI in the setting of CLI. METHODS All TAEI for tissue loss or rest pain (Rutherford classes 4, 5, and 6) from 2004 to 2008 were retrospectively reviewed. Clinical outcomes and patency rates were analyzed by multivariable Cox proportional hazards regression and life table analysis. RESULTS One hundred twenty-three limbs in 111 patients (62% male, mean age 74) were treated. Sixty-seven percent of patients were diabetics, 55% had renal insufficiency, and 21% required hemodialysis. One hundred two limbs (83%) exhibited tissue loss; all others had ischemic rest pain. All patients underwent tibial angioplasty (PTA). Tibial excimer laser atherectomy was performed in 14% of the patients. Interventions were performed on multiple tibial vessels in 20% of limbs. Isolated tibial procedures were performed on 50 limbs (41%), while 73 patients had concurrent ipsilateral superficial femoral artery or popliteal interventions. The mean distal popliteal and tibial runoff score improved from 11.8 ± 3.6 to 6.7 ± 1.6 (P < .001), and the mean ankle-brachial index increased from 0.61 ± 0.26 to 0.85 ± 0.22 (P < .001). Surgical bypass was required in seven patients (6%). The mean follow up was 6.8 ± 6.6 months, while the 1-year primary, primary-assisted, and secondary patency rates were 33%, 50%, and 56% respectively. Limb salvage rate at 1 year was 75%. Factors found to be associated with impaired limb salvage included renal insufficiency (hazard ratio [HR] = 5.7; P = .03) and the need for pedal intervention (HR = 13.75; P = .04). TAEI in an isolated peroneal artery (odds ratio = 7.80; P = .01) was associated with impaired wound healing, whereas multilevel intervention (HR = 2.1; P = .009) and tibial laser atherectomy (HR = 3.1; P = .01) were predictors of wound healing. In patients with tissue loss, 41% achieved complete closure (mean time to healing, 10.7 ± 7.4 months), and 39% exhibited partial wound healing (mean follow up, 4.4 ± 4.8 months) at last follow up. Diabetes, smoking, statin therapy, and revascularization of > 1 tibial vessel had no impact on limb salvage or wound healing. Re-intervention rate was 50% at 1 year. CONCLUSIONS TAEI is an effective treatment for CLI with acceptable limb salvage and wound healing rates, but requires a high rate of reintervention. Patients with renal failure, pedal disease, or isolated peroneal runoff have poor outcomes with TAEI and should be considered for surgical bypass.

Multilevel versus isolated endovascular tibial interventions for critical limb ischemia

OBJECTIVE Endovascular interventions for critical limb ischemia (CLI) continue to have variable reported results. The purpose of this study is to determine the effect of disease level and distribution on the outcomes of tibial interventions. METHODS A retrospective analysis of all tibial interventions done for CLI between 2006 and 2009 was performed. Outcomes of isolated tibial (group I) and multilevel interventions (group II) (femoropopliteal and tibial) were compared. RESULTS Endovascular interventions were utilized to treat 136 limbs in 123 patients for CLI: 54 isolated tibial (85% tissue loss), and 82 multilevel (80% tissue loss). Mean age and baseline comorbidities were comparable. The mean ankle-brachial index (ABI) was significantly lower prior to intervention in group II (0.53 vs 0.74; P < .001) but was similar postintervention (0.86 vs 0.88; P = NS). Wound healing or improvement was achieved in 69% in group I and in 87% in group II (P = .05). Mean overall follow-up was 12.6 ± 5.3 months. Time to healing was significantly longer in group I: 11.5 ± 8.8 months vs 7.7 ± 6.6 months (P = .03). Limb salvage was achieved in 81% of group I and 95% of group II (P = .05). The rate of reintervention was similar (13% vs 18%, P = NS), so was the rate of late surgical conversion (0% vs 6%; P = NS). Limb loss resulted from lack of conduit or initial target vessel for bypass and high-risk systemic comorbidities. Overall mortality rates were similar among both groups. An isolated tibial intervention was a predictor of limb loss at 1 year on multivariate analysis and resulted in a lower rate of limb salvage at 1 year compared with multilevel interventions. Additionally, despite comparable primary patency rates, there was improved secondary patency with multilevel interventions compared with the isolated tibial interventions. Predictors of limb loss in patients treated with isolated tibial intervention included multiple synchronous tibial revascularization (P = .005) and advanced coronary artery disease requiring revascularization (P = .005). CONCLUSIONS Adequate rates of limb salvage can be achieved in patients undergoing multilevel interventions for CLI, and improved patency is seen with multilevel compared to isolated tibial interventions. Patients with isolated tibial disease appear to have a higher incidence of limb loss secondary to poor initial pedal runoff, more extensive distal disease, and severe comorbidities precluding surgical bypass. Other therapeutic strategies should be considered in these patients, including primary amputation or pedal bypass when applicable.

TLR2 and TLR4 Mediate Differential Responses to Limb Ischemia through MyD88-Dependent and Independent Pathways

Introduction The danger signal HMGB1 is released from ischemic myocytes, and mediates angiogenesis in the setting of hindlimb ischemia. HMGB1 is a ligand for innate immune receptors TLR2 and TLR4. While both TLR2 and TLR4 signal through myeloid differentiation factor 88 (MyD88), TLR4 also uniquely signals through TIR-domain-containing adapter-inducing interferon-β (TRIF). We hypothesize that TLR2 and TLR4 mediate ischemic myocyte regeneration and angiogenesis in a manner that is dependent on MyD88 signaling. Methods Mice deficient in TLR2, TLR4, MyD88 and TRIF underwent femoral artery ligation in the right hindlimb. Laser Doppler perfusion imaging was used to assess the initial degree of ischemia and the extent of perfusion recovery. Muscle regeneration, necrosis and fat replacement at 2 weeks post-ligation were assessed histologically and vascular density was quantified by immunostaining. In vitro, endothelial tube formation was evaluated in matrigel in the setting of TLR2 and TLR4 antagonism. Results While control and TLR4 KO mice demonstrated prominent muscle regeneration, both TLR2 KO and TRIF KO mice exhibited marked necrosis with significant inflammatory cell infiltrate. However, MyD88 KO mice had a minimal response to the ischemic insult with little evidence of injury. This observation could not be explained by differences in perfusion recovery which was similar at two weeks in all the strains of mice. TLR2 KO mice demonstrated abnormal vessel morphology compared to other strains and impaired tube formation in vitro. Discussion TLR2 and TRIF signaling are necessary for muscle regeneration after ischemia while MyD88 may instead mediate muscle injury. The absence of TLR4 did not affect muscle responses to ischemia. TLR4 may mediate inflammatory responses through MyD88 that are exaggerated in the absence of TLR2. Additionally, the actions of TLR4 through TRIF may promote regenerative responses that are required for recovery from muscle ischemia.

Surgical and endovascular interventions for nutcracker syndrome.

Nutcracker syndrome is a rare condition of left renal vein entrapment manifesting with hematuria, flank pain, and, occasionally, pelvic congestion in females or varicocele in males. Diagnosis requires a high index of suspicion upon careful history delineation. The gold standard for definite confirmation remains venography with renocaval pressure gradient. Treatment is mainly guided by the severity of symptoms. For the majority of centers, it appears that surgery remains the first-line therapy, however, endovascular alternatives are rapidly evolving into the field with favorable outcomes. This article reviews current concepts on nutcracker syndrome with particular focus on contemporary surgical and endovascular techniques and their outcomes.

Xanthine Oxidoreductase Function Contributes to Normal Wound Healing.

Chronic, nonhealing wounds result in patient morbidity and disability. Reactive oxygen species (ROS) and nitric oxide (NO) are both required for normal wound repair, and derangements of these result in impaired healing. Xanthine oxidoreductase (XOR) has the unique capacity to produce both ROS and NO. We hypothesize that XOR contributes to normal wound healing. Cutaneous wounds were created in C57Bl6 mice. XOR was inhibited with dietary tungsten or allopurinol. Topical hydrogen peroxide (H2O2, 0.15%) or allopurinol (30 µg) was applied to wounds every other day. Wounds were monitored until closure or collected at d 5 to assess XOR expression and activity, cell proliferation and histology. The effects of XOR, nitrite, H2O2 and allopurinol on keratinocyte cell (KC) and endothelial cell (EC) behavior were assessed. We identified XOR expression and activity in the skin and wound edges as well as granulation tissue. Cultured human KCs also expressed XOR. Tungsten significantly inhibited XOR activity and impaired healing with reduced ROS production with reduced angiogenesis and KC proliferation. The expression and activity of other tungsten-sensitive enzymes were minimal in the wound tissues. Oral allopurinol did not reduce XOR activity or alter wound healing but topical allopurinol significantly reduced XOR activity and delayed healing. Topical H2O2 restored wound healing in tungsten-fed mice. In vitro, nitrite and H2O2 both stimulated KC and EC proliferation and EC migration. These studies demonstrate for the first time that XOR is abundant in wounds and participates in normal wound healing through effects on ROS production.

Persistent sciatic artery aneurysm treated with concomitant tibial bypass and vascular plug embolization

The presence of a persistent sciatic artery is a rare congenital vascular malformation. Complications associated with aneurysmal degeneration of this aberrant vessel include rupture, thrombosis, and embolization with obliteration of outflow vessels. We describe the case of an 82-year-old female presenting with critical limb ischemia due to embolization from a partially thrombosed persistent sciatic artery aneurysm. Successful treatment was achieved via a common femoral to posterior tibial artery bypass with the great saphenous vein and vascular plug embolization of the aneurysm.

P2Y2 nucleotide receptor mediates arteriogenesis in a murine model of hind limb ischemia

OBJECTIVE Arteriogenesis represents the maturation of preformed vascular connections in response to flow changes and shear stress. These collateral vessels can restore up to 60% of the native blood flow. Shear stress and vascular injury can induce the release of nucleotides from vascular smooth muscle cells and platelets that can serve as signaling ligands, suggesting they may be involved in mediating arteriogenesis. The P2Y2 nucleotide receptor (P2Y2R) has also been shown to mediate smooth muscle migration and arterial remodeling. Thus, we hypothesize that P2Y2R mediates arteriogenesis in response to ischemia. METHODS Hind limb ischemia was induced by femoral artery ligation (FAL) in C57Bl/6NJ or P2Y2R negative mice (P2Y2(-/-)). Hind limb perfusion was measured with laser Doppler perfusion imaging and compared with the sham-operated contralateral limb immediately and at 3, 7, 14, 21, and 28 days after ligation. Collateral vessel size was measured by Microfil casting. Muscle specimens were harvested and analyzed with immunohistochemistry for Ki67, vascular cell adhesion molecule, macrophages, and muscle viability by hematoxylin and essoin stain. RESULTS Hind limb ischemia induced by FAL in C57Bl/6NJ mice resulted in significant ischemia as measured by laser Doppler perfusion imaging. There was rapid recovery to nearly normal levels of perfusion by 2 weeks. FAL in P2Y2(-/-) mice resulted in severe ischemia with greater tissue loss. Recovery of perfusion was impaired, achieving only 40% compared with wild-type mice by 28 days. Collateral vessels in the P2Y2(-/-) mice were underdeveloped, with reduced vascular cell proliferation and smaller vessel size. The collaterals were ∼65% the size of wild-type collateral vessels (P = .011). Angiogenesis at 28 days in the ischemic muscle, however, was greater in the P2Y2(-/-) mice (P < .001), possibly related to persistent ischemia leading and angiogenic drive. Early macrophage recruitment was reduced by nearly 70% in P2Y2(-/-) despite significantly more myocyte necrosis. However, inflammation was greater at 28 days in the P2Y2(-/-) mice. CONCLUSIONS P2Y2R deficiency does not alter baseline collateral vessel formation but does significantly impair collateral maturation, with resultant persistent limb ischemia despite enhanced angiogenesis. These findings reinforce the importance of arteriogenesis in the recovery of perfusion in ischemic tissues compared with angiogenesis. They also support the role of P2Y2R in mediating this process. The mechanism by which P2Y2R mediates arteriogenesis may involve the recruitment of inflammatory cells to the ischemic tissues, which is essential to arteriogenesis. Approaches to target P2Y2R may yield new therapeutic strategies for the treatment of arterial occlusive disease.

A modified rat model of hindlimb ischemia for augmentation and functional measurement of arteriogenesis

Arteriogenesis (collateral artery development) is an adaptive pathway critical for salvage of tissue in the setting of arterial occlusion. Rodent models of arteriogenesis typically involve an experimental occlusion (ligation) of a hindlimb artery and then rely on indirect measures such as laser Doppler perfusion imaging to assess blood flow recovery. Unfortunately, the more commonly utilized measures of distal tissue perfusion at rest are unable to account for hemodynamic and vasoactive variables and thus provide an incomplete assessment of collateral network capacity. We provide a detailed description of modifications to the commonly used model of femoral artery ligation. These serve to alter and then directly assess collateral network’s hemodynamic capacity. By incorporating an arteriovenous fistula distal to the arterial ligation, arterial growth is maximized. Hindlimb perfusion may be isolated to measure minimum resistance of flow around the arterial occlusion, which provides a direct measure of collateral network capacity. Our results reinforce that arteriogenesis is driven by hemodynamic variables, and it can be reliably augmented and measured in absolute terms. Using these modifications to a widely used model, functional arteriogenesis may be more directly studied.