Impact of Serum Zinc Level and Oral Zinc Supplementation on Clinical Outcomes in Patients Undergoing Infrainguinal Bypass for Chronic Limb-Threatening Ischemia.

BACKGROUND: Zinc (Zn) has been reported to play an important role in wound healing (WH). Nevertheless, the effect of Zn in chronic limb-threatening ischemia (CLTI) patients is unclear. This study investigated the effect of Zn on the clinical outcomes of CLTI patients undergoing bypass surgery.Methods and Results: This study reviewed 111 consecutive patients who underwent an infrainguinal bypass from 2012 to 2020. Patients with Zn deficiency (serum Zn level <60 µg/dL) received oral Zn supplementation and maintained a normal level until WH. This study aimed to explore: (1) the effect of Zn deficiency; and (2) Zn supplementation in Zn-deficient patients on the clinical outcomes of this cohort. Patients with Zn deficiency, Zn supplementation, and no Zn supplementation despite Zn deficiency accounted for 48, 21, and 42 patients, respectively. (1) Zn deficiency was associated with WH (HR, 0.47; 95% CI, 0.29-0.78: P=0.003), major adverse limb events (MALE) (HR, 2.53; 95% CI, 1.26-5.09: P=0.009), and major amputation or death (HR, 3.17; 95% CI, 1.51-6.63: P=0.002). (2) Zn supplementation was positively related to WH (HR, 2.30; 95% CI, 1.21-4.34: P=0.011). This result was confirmed using propensity score matching (HR, 2.24; 95% CI, 1.02-4.87: P=0.043). CONCLUSIONS: The current study revealed that Zn level was associated with clinical outcomes in CLTI patients after bypass surgery. Oral Zn supplementation could improve WH in these patients.

Endovenous Laser Ablation with and Without Concomitant Phlebectomy for the Treatment of Varicose Veins: A Retrospective Analysis of 954 Limbs.

BACKGROUND: Endovenous laser ablation (EVLA) with concomitant phlebectomy is commonly performed in many institutions. However, phlebectomy is associated with cosmetic complications such as surgical scarring, hemorrhage, and hematoma. This study aims to compare the need for additional sclerotherapy during follow-up after EVLA with and without concomitant phlebectomy. METHODS: Between November 2013 and December 2018, we performed EVLA on 1,363 limbs in 1,009 patients with symptomatic primary varicose veins, of which 954 limbs in 771 patients with great saphenous vein (GSV) or small saphenous vein (SSV) insufficiency were included in this study. Data were collected prospectively and supplemented with retrospective medical record review. Demographic and clinical characteristic profiles were collected. The outcomes of EVLA with or without concomitant phlebectomy were compared. Logistic regression was used to assess predictors for additional sclerotherapy after EVLA. RESULTS: CEAP classification (P < 0.001), operative time (P < 0.001), laser device type (P < 0.001), length of the treated vein (P < 0.001), linear endovenous energy density (P < 0.001), and tumescent local anesthesia volume (P < 0.001) differed significantly. Pain after EVLA was significantly more frequent in the nonphlebectomy group than in the phlebectomy group (P = 0.005). During follow-up, 34 of 954 limbs (3.6%) underwent additional sclerotherapy for residual visible varicose veins after EVLA. No statistical difference was found in the rate of additional sclerotherapy between the groups (P = 0.849). Logistic regression showed that female sex (odds ratio [OR], 6.18; 95% confidence interval [CI], 1.86-20.6; P = 0.003) is significantly associated with additional sclerotherapy, and concomitant phlebectomy is not a significant predictor of additional sclerotherapy (OR, 0.844; 95% CI, 0.375-1.90; P = 0.682). CONCLUSIONS: Patient preference for additional sclerotherapy was comparable between those who underwent EVLA with and without concomitant phlebectomy. This result supports our present strategy of avoiding simultaneous phlebectomy at the time of primary EVLA.

Zinc Deficiency and Clinical Outcome After Infrainguinal Bypass Grafting for Critical Limb Ischemia.

Background: The aim of this study was to identify a relationship between zinc (Zn) deficiency and clinical outcome in patients with critical limb ischemia (CLI). Methods and Results: Forty-five limbs from 44 patients with CLI who underwent de novo infrainguinal bypass grafting (IBG) were retrospectively reviewed. The patients were divided into a Zn deficiency group (ZD group: Zn <60 µg/dL) and a Zn sufficiency group (ZS group: Zn ≥60 µg/dL). Graft patency, limb salvage (LS), amputation-free survival (AFS), and wound healing were compared between the groups. LS and AFS were examined to identify whether Zn deficiency was an independent predictor. The preoperative factors potentially predictive of Zn deficiency were also analyzed. Twenty-four limbs were categorized into the ZD group. Patients in the ZD group were more likely to have undergone hemodialysis (HD) and have lower serum albumin. The surgical procedures were not significantly different between the groups. Patency, LS, AFS, and complete wound healing rates were significantly lower in the ZD group. Zn deficiency was a negative predictor of LS. Age >75 years and HD were identified as predictors of Zn deficiency. Conclusions: Zn deficiency was associated with poor clinical outcome. Zn supplementation may improve clinical outcomes during IBG for CLI.

Mulberry leaf ameliorates the expression profile of adipocytokines by inhibiting oxidative stress in white adipose tissue in db/db mice.

Previous study showed that mulberry (Morus Alba L.) leaf (ML) ameliorates atherosclerosis in apoE(-/-) mice. Although the adipocytokine dysregulation is an important risk factor for atherosclerotic cardiovascular disease, the effect of ML on metabolic disorders related to adipocytokine dysregulation and inflammation has not been studied. Therefore, we studied the effects of ML in metabolic disorders and examined the mechanisms by which ML ameliorates metabolic disorders in db/db mice. We treated db/db mice with ML, pioglitazone, or both for 12 weeks and found that ML decreased blood glucose and plasma triglyceride. Co-treatment with ML and pioglitazone showed additive effects compared with pioglitazone. Moreover, their co-treatment attenuated the body weight increase observed under the pioglitazone treatment. ML treatment also increased the expression of adiponectin, and decreased the expression of TNF-alpha, MCP-1, and macrophage markers in white adipose tissue (WAT). Furthermore, ML decreased lipid peroxides and the expression of NADPH oxidase subunits in WAT and liver. Their co-treatment enhanced these effects. Thus, ML ameliorates adipocytokine dysregulation at least in part through inhibiting oxidative stress in WAT of db/db mice, and that ML may be a basis for a pharmaceutical for the treatment of the metabolic syndrome as well as reducing adverse effects of pioglitazone.

Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition.

BACKGROUND: Recent studies suggest that statins can protect the vasculature in a manner that is independent of their lipid-lowering activity through inhibition of the small guanosine triphosphate-binding protein, Rho, and Rho-associated kinase. Little information is available on the inhibitory effect of statins on vein graft intimal hyperplasia, the main cause of late graft failure after bypass grafting. We therefore examined the effects of a hydrophilic statin on vein graft intimal hyperplasia in vivo and Rho-kinase activity in vitro. METHODS: In the first experiment, rabbits were randomized to a control group (n = 7) that was fed regular rabbit chow or to a pravastatin group (n = 7) that was fed regular rabbit chow supplemented with 10 mg/kg pravastatin sodium. The branches of the jugular vein were ligated and an approximately 3-cm segment of the jugular vein was taken for an autologous reversed-vein graft. The carotid artery was cut and replaced with the harvested autologous jugular vein. At 2 and 4 weeks after the operation, vein grafts in both groups were harvested, and intimal hyperplasia of the vein grafts was assessed. In the second experiment, human umbilical vein endothelial cells and vascular smooth muscle cells were cultured and then treated with 1 micromol/L and 30 micromol/L pravastatin for 24 hours and harvested. Immunoblotting was performed on the resulting precipitates. Quantitative evaluation of phosphorylated myosin binding subunit and endothelial nitric oxide synthase was performed by densitometric analysis. RESULTS: We demonstrated that oral administration of the hydrophilic statin pravastatin to normocholesterolemic rabbits inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts 4 weeks after implantation (pravastatin group, 39.5 +/- 3.5 microm vs control group, 64.0 +/- 7.1 microm; n = 7; P < .05) and suppressed cell proliferation and apoptosis in the neointima 2 weeks after implantation. In addition, we found that pravastatin inhibited Rho-kinase activity and accelerated endothelial nitric oxide synthase expression in human umbilical vein endothelial cells but did not inhibit Rho-kinase activity in vascular smooth muscle cells. CONCLUSIONS: These novel findings clearly demonstrate that a hydrophilic statin can suppress intimal hyperplasia of the vein graft in vivo and also show endothelial cell-tropic inhibition of Rho-kinase in vitro. Furthermore, these results strongly support the clinical use of hydrophilic statins to prevent intimal hyperplasia of the vein graft after bypass grafting. CLINICAL RELEVANCE: Late graft failure caused by neointimal hyperplasia limits the efficacy of vein grafting. Various treatments were examined to reduce neointimal hyperplasia, but a standard clinical treatment has not yet been established. We report here the inhibitory effect of pravastatin on the development of vein graft intimal hyperplasia. In addition, we demonstrate that pravastatin showed endothelial cell-tropic benefits through both the inhibition of Rho-kinase activity and acceleration of eNOS expression in vitro. Because the clinical benefits and safety of pravastatin have been established to a certain extent through long-term clinical usage, pravastatin may soon become standard treatment after vein bypass grafting.