FC 107SNF472 ATTENUATES THE PROGRESSION OF FEMORAL ARTERY CALCIFICATION AND RECOVERS LIMB BLOOD PERFUSION AND WALKING ABILITY IN A RAT MODEL OF PERIPHERAL ARTERY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Firas Bassissi ◽  
Miguel David Ferrer Reynes ◽  
M Mar Pérez ◽  
Marc Blasco ◽  
Joan Perelló ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Femoral Artery ◽  
Rat Model ◽  
Blood Perfusion ◽  
Limb Ischemia ◽  
Arterial Calcification ◽  
Walking Ability ◽  
Peripheral Artery ◽  
Femoral Arteries ◽  
Artery Disease

Abstract Background and Aims Peripheral artery disease (PAD) is a common co-morbidity in end-stage kidney disease (ESKD) patients undergoing dialysis. The prominent vascular calcification in these patients is associated with severity of symptoms and adverse outcomes. Although there are medical therapies approved for PAD, none of them has been specifically approved por PAD-ESKD. For example, cilostazol is approved for PAD but its use is limited in PAD-ESKD patients. Surgical interventions are challenging in these patients due to their specific vascular calcification and show worse outcomes. Therefore, the aims of this study were to evaluate the effects of the investigational drug SNF472, a selective inhibitor of vascular calcification, on blood perfusion and limb functional recovery in a Vitamin D3 (VitD)-induced rat model of arterial calcification and limb ischemia. Method Three consecutives daily subcutaneous (s.c) doses of VitD were administered to 66 male Sprague Dawley rats to induce limb ischemia. Rats were randomized into four groups at day 5 after the start of VitD treatment (when all parameters were measured in a satellite group) and were treated for nine days with placebo s.c., placebo peroral (p.o.), SNF472 (40 mg/kg/day, s.c.) or cilostazol (40 mg/kg/day, p.o.). An additional control group did not receive VitD (sham) and was administered with placebo s.c. during these last nine days. Posterior limb blood perfusion was measured using laser Doppler imaging at baseline (before calcification induction), day 4 (before treatment start) and day 13 (end of treatment). Walking ability was evaluated by measuring Maximum Walking Distance (MWD) and Maximum Walking Time (MWT) using a rat treadmill at baseline, day 4 and day 11. Rats were sacrificed at day 13, and heart and femoral arteries were collected for calcium analysis. Results Administration of VitD induced heart and femoral artery calcification by day 5. This calcification was associated with decreased limb blood perfusion and impairment of walking ability (both MWT and MWD) compared to sham. Treatment with SNF472 inhibited calcification progression in femoral arteries by 41% and in heart by 56% compared to placebo. The inhibition of calcification progression by SNF472 led to a 29% increase in limb blood perfusion (p< 0.001) and a significant improvement in walking ability (49% in MWD and 43% in MWT; p< 0.05) compared to placebo. Calcification inhibition in femoral arteries was positively correlated with both MWD and MWT (p< 0.0001). No effects of cilostazol were observed in tissue calcification, limb blood perfusion or walking ability. Conclusion SNF472 attenuates the progression of vascular calcification and improves blood perfusion and the functional parameters MWT and MWD in a rat model of PAD vascular calcification. These results support investigation of SNF472 as a potential therapy for PAD-ESKD patients who have vascular dysfunction due to a high degree of arterial calcification.

scholarly journals P1234SNF472 IMPROVES LIMB BLOOD PERFUSION AND WALKING ABILITY IN A PERIPHERAL ARTERY DISEASE VASCULAR CALCIFICATION RAT MODEL

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Firas Bassissi ◽  
Miguel David Ferrer Reynes ◽  
M Mar Pérez ◽  
Joan Perelló ◽  
Carolina Salcedo
Keyword(s):  
Peripheral Artery Disease ◽  
Vascular Calcification ◽  
Rat Model ◽  
Blood Perfusion ◽  
Walking Distance ◽  
Arterial Calcification ◽  
Walking Ability ◽  
Peripheral Artery ◽  
Increased Risk ◽  
Artery Disease

Abstract Background and Aims Peripheral Artery disease (PAD) is a common vascular disease associated with functional impairment and increased risk of cardiovascular events in End Stage Kidney Disease (ESKD) patients undergoing dialysis. Poor limb salvage outcomes and high post-amputation mortality in hemodialysis (HD) patients highlight the need for earlier medical therapies. Cilostazol and pentoxifylline are approved for PAD. Their use in HD patients stays limited and cilostazol use requires caution in this population. Clinical studies demonstrate associations between arterial calcification and adverse outcomes in PAD patients. SNF472, a selective calcification inhibitor that interferes in the formation and growth of hydroxyapatite, is in Phase 3 for calciphylaxis treatment. This study aims to evaluate the effects of SNF472 on limb functional recovery and blood perfusion in a Vitamin D3 (VitD)-induced arterial calcification rat model. Method Arterial calcification was induced in 32 Sprague Dawley rats by 3 consecutive daily s.c. doses of 120 kIU/kg VitD. Rats were divided into four groups and treated during 12 days by: placebo s.c, placebo p.o, SNF472 (20 mg/kg/day, s.c.) or cilostazol (20 mg/kg/day, p.o.). An additional group of 8 rats without VitD received vehicle only (sham). Efficacy was evaluated at day 12 and 17 (5 days after treatment stop). Posterior limb blood perfusion was measured using Laser Doppler Imaging and limb walking ability was evaluated by measuring Maximum Walking Distance (MWD) and Maximum Walking Time (MWT) using a treadmill. Rats were sacrificed at day 26 (14 days after treatment stop), and aortas were collected for calcium analysis. Results VitD-induced arterial calcification was associated with decreased blood perfusion and impairment of limb walking ability (MWT and MWD) compared to sham. SNF472 reduced aorta calcification by 41% compared to placebo. No effects of cilostazol on vascular calcification were observed. The inhibition of calcification in SNF472-treated animals was associated with significant higher limb blood perfusion compared to placebo or Cilostazol (1.28 and 1.37-fold higher, respectively at day 12: p< 0.001) and it was translated into a significant improvement in walking ability compared to placebo (515±114 meters vs 334±187 meters, respectively: p<0.05). Conclusion SNF472 shows improvements in vascular calcification, blood perfusion and a functional parameter like walking distance in a PAD vascular calcification rat model. These results suggest that SNF472 may represent a new therapeutic approach for the treatment of PAD associated with high vascular calcification such as in renal disease.

scholarly journals SNF472 Improves Limb Blood Perfusion and Walking Ability and Inhibits Progression of Calcification in Femoral Arteries in a Rat Model of Peripheral Artery Disease

2021 ◽  
Vol 74 (3) ◽  
pp. e62-e63
Author(s):  
Firas Bassissi ◽  
Miguel D. Ferrer ◽  
M. Mar Perez ◽  
Marc Blasco ◽  
Joan Perelló ◽  
...  
Keyword(s):  
Peripheral Artery Disease ◽  
Rat Model ◽  
Blood Perfusion ◽  
Walking Ability ◽  
Peripheral Artery ◽  
Femoral Arteries ◽  
Artery Disease

Abstract 17955: Thereapeutic Angiogenesis Induced by Human Trx-1 Gene in Mice Hind Limb Ischemia Model: Preclinical Study for Treatment of Peripheral Artery Disease

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Mahesh Thirunavukkarasu ◽  
Inam A Shaikh ◽  
Vaithinathan Selvaraju ◽  
J.Alexandar Palesty ◽  
Nilanjana Maulik
Keyword(s):  
Gene Therapy ◽  
Peripheral Artery Disease ◽  
Femoral Artery ◽  
Hind Limb ◽  
Blood Perfusion ◽  
Limb Ischemia ◽  
Heme Oxygenase 1 ◽  
Peripheral Artery ◽  
Artery Ligation ◽  
Artery Disease

Introduction: Peripheral artery disease affects 12-20% Americans over the age of 60. Thioredoxin-1 (Trx-1) is a class of small redox proteins. We have demonstrated earlier that Trx-1 reduces oxidative stress resulting in less inflammation and increased angiogenesis in cardiac muscle via heme oxygenase-1 (HO-1) and VEGF after myocardial infarction. In the current study, we evaluate the effect of Trx-1 on post-ischemic hindlimb recovery. Methods: Peripheral artery disease was mimicked using a hindlimb ischemia (HLI) model. Wild type (WT) and Trx-1 transgenic (Trx-1Tg/+) mice (8-12 weeks old) were subjected to femoral artery ligation. Following surgery, mice were observed for 5 weeks. Serial laser doppler images were obtained, and perfusion ratios between the ischemic and non-ischemic limbs were calculated at set time intervals. The perfusion ratios were compared between WT and Trx-1Tg/+ groups. Immunohistochemical analysis of the skeletal muscle was performed to quantify the extent of fibrosis, capillary and arteriolar density 35 days after surgery. In addition, another set of experiments was designed with Ad.Trx-1 gene therapy after femoral artery ligation to study the molecular mechanism of neovascularization with Trx-1. Results: The recovery of hind limb perfusion was significantly increased in Trx-1Tg/+ mice at day 7 (0.19 ± 0.03 vs. 0.36 ± 0.07 (n=12-9), day-21 (0.37 ± 0.05 vs. 0.62 ± 0.03 (n=12-9), and day 28 (0.40 ± 0.04 vs. 0.79 ± 0.04 (n=10-9); p<0.05). Capillary density [1265 ± 87.8 vs. 762.4 ± 86.6 counts/mm2 ; (n=5); p<0.05] and arteriolar density [36.2 ± 2.96 vs. 22± 1.33 counts/mm2 ; (n=5); p<0.05] staining showed significant increase in Trx-1Tg/+ mice as compared to WT mice. Picrosirrus Red and immunofluorescence staining showed decreased fibrosis [8.3 ± 0.46 vs. 22.2 ± 1.04 (n=5); p<0.0001] and increased HO-1 expression respectively in Trx-1Tg/+ mice group as compared to WT mice, respectively. Trx-1 gene therapy study also revealed by Western blot analysis, increased Trx-1 (4.2 fold) and HO-1 (8.2 fold) expression in Ad.Trx-1-HLI as compared to Ad.LacZ-HLI. Conclusions: Our results suggest that Trx-1 is a potential therapeutic agent to increase blood perfusion and angiogenesis for the treatment of critical limb ischemia patients.

Abstract 722: Treatment of Acute and Chronic Limb Ischemia with Intermedin (IMD) in Mouse Models

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Luyu Yao ◽  
Honglin Dong ◽  
Allen Gu ◽  
Xin Gu ◽  
Kai Yao ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Blood Perfusion ◽  
Limb Ischemia ◽  
Control Group ◽  
Silk Suture ◽  
Hindlimb Ischemia ◽  
Occlusion Model ◽  
Before And After ◽  
Artery Disease ◽  
The One

Objectives: This experiment proposes a novel mouse model to simulate long-term chronic ischemia caused by peripheral artery disease (PAD) using a partial ligation method to narrow down the femoral artery lumen in C57Bl/6 mice. This model will be compared to the typical occlusion model while testing Intermedin (IMD) as a possible treatment for ischemia. Methods: Partial hindlimb ligation technique: we use a strand of 11-0 nylon sutures to pierce the middle of the artery and suture half of the artery shut at both the proximal and distal end of the femoral artery. The typical occlusion model: we use a 7-0 silk suture to completely ligate the distal and proximal femoral artery. Hindlimb blood flow was monitored daily by Laser Doppler perfusion monitor before and after the surgery. IMD was administered at 150 μg/kg, ip, immediately following ligation and twice daily afterwards for up to one week, while in the control group saline was injected instead of IMD. Gastrocnemius muscle samples were collected at day 3 and day 7 for histology and molecular biology study. Results: Ischemic/non-ischemic leg blood perfusion ratio in the partial ligation model is significantly higher than in the typical model. It is also significantly increased in IMD-treated groups in both models. Compared to the tissue in complete ligation models, it is apparent that partial ligation model tissue is less severely affected upon initial ligation but maintains ischemia over the one week testing period as would be expected. Compared to the untreated ischemia groups in acute and chronic hindlimb ischemia models, IMD-treated animals had less severe ischemic injuries. Conclusion: Our study indicates that our chronic hindlimb ischemia model was successful with expected less ischemia status than complete occlusion. The partial occlusion model presented here more closely mimics human PAD, where atherosclerotic plaque builds up slowly, resulting in a lower pressure difference between the proximal and distal artery preventing adequate shunting of the blood into collateral circulation. Moreover, our study suggests that IMD has promise as a therapeutic treatment in acute and chronic hindlimb ischemia models to prevent necrosis in muscle tissue following ischemic events.

scholarly journals Association of arterial calcification with chronic limb ischemia in patients with peripheral artery disease

2018 ◽  
Vol 67 (2) ◽  
pp. 507-513 ◽  
Author(s):  
Sara L. Zettervall ◽  
Andre P. Marshall ◽  
Paul Fleser ◽  
Raul J. Guzman
Keyword(s):  
Peripheral Artery Disease ◽  
Limb Ischemia ◽  
Arterial Calcification ◽  
Peripheral Artery ◽  
Artery Disease ◽  
Chronic Limb Ischemia

scholarly journals Vascular Complications of Lower Limb Ischemia in Patients with Femoral Venoarterial Extracorporeal Membrane Oxygenation

2020 ◽  
Vol 23 (3) ◽  
pp. E305-E309
Author(s):  
Xiaozu Liao ◽  
Zhou Cheng ◽  
Liqiang Wang ◽  
Binfei Li ◽  
Weizhao Huang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Femoral Artery ◽  
Lower Limb ◽  
Independent Risk Factor ◽  
Limb Ischemia ◽  
Peripheral Artery ◽  
Lower Limb Ischemia ◽  
Ischemia Group ◽  
Artery Disease ◽  
Va Ecmo

Background: Lower limb ischemia in patients with extracorporeal membrane oxygenation (ECMO) via femoral artery catheterization negatively affects patient mortality and survivors’ quality of life [Gulkarov 2020]. In this study, ECMO was established via femoral artery catheterization. This study aimed to identify the risk factors of lower limb ischemia to provide sufficient evidence for its prevention. Methods: All patients with venoarterial (VA) ECMO via femoral artery catheterization in Zhongshan People’s Hospital from January 2008 to November 2019 retrospectively were analyzed. Patients’ general information and ECMO-related information were obtained, and the main outcome variables were survival and discharge and intubation-related adverse events (limb ischemia and incision bleeding). Logistic regression analysis was used to determine the independent risk factors of limb ischemia in patients with VA ECMO. Results: A total of 179 (98 [54.7%] men and 81 [45.3%] women) eligible patients were included in this study. Moreover, a total of 90 patients (48.9%) had low cardiac output, 41 (22.3%) had acute myocardial infarction, and 33 (17.9%) had fulminant myocarditis. Eighty-six (48.04%) patients survived to hospital discharge, 36 (20.11%) had limb ischemia, and 42 (23.46%) had incision bleeding. Furthermore, the ECMO-assisted time was 114.23 ± 67.88 hours. There was no significant difference in age, sex, and Sequential Organ Failure Assessment score between the limb ischemia group and the non-limb ischemia group. Multivariate logistic regression analysis showed that peripheral artery disease (odds ratio, 27.12; 95% confidence interval, 5.614–130.96) was an independent risk factor of limb ischemia in patients with ECMO. Conclusion: Limb ischemia is a common complication in patients with VA ECMO, and peripheral artery disease is an independent risk factor of limb ischemia in patients with VA ECMO via femoral artery catheterization.

scholarly journals Angiogenin—A Proposed Biomarker for Cardiovascular Disease—Is Not Associated With Long-Term Survival in Patients With Peripheral Artery Disease

Angiology ◽  
2021 ◽  
pp. 000331972110043
Author(s):  
Clemens Höbaus ◽  
Gerfried Pesau ◽  
Bernhard Zierfuss ◽  
Renate Koppensteiner ◽  
Gerit-Holger Schernthaner
Keyword(s):  
Peripheral Artery Disease ◽  
Cox Regression ◽  
Ankle Brachial Index ◽  
Limb Ischemia ◽  
Cross Sectional Study ◽  
Enzyme Linked Immunosorbent Assay ◽  
Peripheral Artery ◽  
Cross Sectional ◽  
Term Survival ◽  
Artery Disease

We evaluated angiogenin as a prospective biomarker in peripheral artery disease (PAD) patients with and without claudication symptoms. A pilot study suggested an elevation of angiogenin in critical limb ischemia. However, in PAD patients, the predictive value of angiogenin has not yet been evaluated. For this purpose, 342 patients with PAD (age: 69 ± 10 years, 34.5% women) were followed-up for 7 years in a cross-sectional study. Angiogenin was measured by enzyme-linked immunosorbent assay. All-cause and cardiovascular mortality were analyzed by Cox regression. Angiogenin levels were higher in men ( P = .001) and were associated with patient waist-to-hip ratio ( P < .001), fasting triglycerides ( P = .011), and inversely with estimated glomerular filtration rate ( P = .009). However, angiogenin showed no association with age, characteristics of diabetes, markers of lipid metabolism, or C-reactive protein. Angiogenin did not correlate with markers of angiogenesis such as vascular endothelial growth factor, angiopoietin-2, or tie-2. Furthermore, angiogenin was not associated with PAD Fontaine stages or with patient ankle-brachial index in addition to all-cause mortality (hazard ratio [HR] = 1.09 [95% CI: 0.89-1.34]) or cardiovascular morality (HR = 1.05 [0.82-1.35]). These results suggest that angiogenin does not provide further information regarding outcome prediction in patients with PAD.

Multi-Level Lower Extremity Arterial Revascularization Via Retrograde Pedal Access Under Local Anesthesia in a Patient With Severe Cardiopulmonary Comorbidities: A Case Report

2021 ◽  
pp. 153857442110264
Author(s):  
Hee Korleski ◽  
Laura DiChiacchio ◽  
Luiz Araujo ◽  
Michael R. Hall
Keyword(s):  
Case Report ◽  
General Anesthesia ◽  
Peripheral Artery Disease ◽  
Critical Limb Ischemia ◽  
Treatment Modality ◽  
Conventional Treatment ◽  
Limb Ischemia ◽  
Peripheral Artery ◽  
Endovascular Revascularization ◽  
Artery Disease

Background: Chronic limb-threatening ischemia is a severe form of peripheral artery disease that leads to high rates of amputation and mortality if left untreated. Bypass surgery and antegrade endovascular revascularization through femoral artery access from either side are accepted as conventional treatment modalities for critical limb ischemia. The retrograde pedal access revascularization is an alternative treatment modality useful in specific clinical scenarios; however, these indications have not been well described in literature. This case report highlights the use of retrograde pedal access approach as primary treatment modality in a patient with an extensive comorbidities precluding general anesthesia nor supine positioning. Case Presentation: The patient is a 60-year-old female with multiple severe cardiopulmonary comorbidities presenting with dry gangrene of the right great toe. Her comorbidities and inability to tolerate supine positioning precluded her from receiving open surgery, general anesthesia or monitored sedation, or percutaneous femoral access. Rather, the patient underwent ankle block and retrograde endovascular revascularization via dorsalis pedis artery access without post-operative complications. Discussion: The prevalence of comorbidities related to peripheral artery disease is increasing and with it the number of patients who are not optimal candidates for conventional treatment methods for critical limb ischemia. The retrograde pedal access revascularization as initial treatment modality offers these patients an alternative limb salvaging treatment option.

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