Abstract:Objectives The clinical presentation of peripheral artery disease (PAD) and chronic venous insufficiency (CVI) can overlap and the conditions may co-exist. The purpose of our study was to investigate the prevalence and clinical significance of concomitant CVI in patients with PAD examined with runoff MR angiography (MRA). Methods We analysed 180 patients (median age 69 years, range 27 to 91) with known or suspected PAD who underwent MRA at our institution between 2012 and 2018. MRA datasets were re-evaluated f… Show more
“…As we did not observe any evidence of microvascular thrombosis on histological examination, the supranormal D-dimer levels likely reflect recent surgical intervention. Of note, coagulation of the femoral vein in conjunction with the femoral artery was performed due to ease of the operation and may be clinically relevant as chronic venous insufficiency is a common comorbidity in patients with PAD ( 42 ). Regarding inflammation, PCR array demonstrated that E-sel/AAV2/2 modulated the inflammatory gene profile of ischemic limb tissue with an overall dampening or “cooling” effect on heatmap analysis.…”
For patients with chronic limb-threatening ischemia and limited revascularization options, alternate means for therapeutic angiogenesis and limb salvage are needed. E-selectin is a cell adhesion molecule that is critical for inflammation and neovascularization in areas of wound healing and ischemia. Here, we tested the efficacy of modifying ischemic limb tissue by intramuscular administration of E-selectin/AAV2/2 (adeno-associated virus serotype 2/2) to modulate angiogenic and inflammatory responses in a murine hindlimb gangrene model. Limb appearance, reperfusion, and functional recovery were assessed for 3 weeks after induction of ischemia. Mice receiving E-selectin/AAV2/2 gene therapy had reduced gangrene severity, increased limb and footpad perfusion, enhanced recruitment of endothelial progenitor cells, and improved performance on treadmill testing compared to control group. Histologically, E-selectin/AAV2/2 gene therapy was associated with increased vascularity and preserved myofiber integrity. E-selectin/AAV2/2 gene therapy also upregulated a panel of pro-angiogenic genes yet downregulated another group of genes associated with the inflammatory response. This novel gene therapy did not induce adverse effects on coagulability, or hematologic, hepatic, and renal function. Our findings highlight the potential of E-selectin/AAV2/2 gene therapy for improving limb perfusion and function in patients with chronic limb-threatening ischemia.
“…As we did not observe any evidence of microvascular thrombosis on histological examination, the supranormal D-dimer levels likely reflect recent surgical intervention. Of note, coagulation of the femoral vein in conjunction with the femoral artery was performed due to ease of the operation and may be clinically relevant as chronic venous insufficiency is a common comorbidity in patients with PAD ( 42 ). Regarding inflammation, PCR array demonstrated that E-sel/AAV2/2 modulated the inflammatory gene profile of ischemic limb tissue with an overall dampening or “cooling” effect on heatmap analysis.…”
For patients with chronic limb-threatening ischemia and limited revascularization options, alternate means for therapeutic angiogenesis and limb salvage are needed. E-selectin is a cell adhesion molecule that is critical for inflammation and neovascularization in areas of wound healing and ischemia. Here, we tested the efficacy of modifying ischemic limb tissue by intramuscular administration of E-selectin/AAV2/2 (adeno-associated virus serotype 2/2) to modulate angiogenic and inflammatory responses in a murine hindlimb gangrene model. Limb appearance, reperfusion, and functional recovery were assessed for 3 weeks after induction of ischemia. Mice receiving E-selectin/AAV2/2 gene therapy had reduced gangrene severity, increased limb and footpad perfusion, enhanced recruitment of endothelial progenitor cells, and improved performance on treadmill testing compared to control group. Histologically, E-selectin/AAV2/2 gene therapy was associated with increased vascularity and preserved myofiber integrity. E-selectin/AAV2/2 gene therapy also upregulated a panel of pro-angiogenic genes yet downregulated another group of genes associated with the inflammatory response. This novel gene therapy did not induce adverse effects on coagulability, or hematologic, hepatic, and renal function. Our findings highlight the potential of E-selectin/AAV2/2 gene therapy for improving limb perfusion and function in patients with chronic limb-threatening ischemia.
“…Common macrovascular complications of DM that affect the lower extremity include PAD and chronic venous insufficiency (CVI), which may lead to lower extremity amputation (Figure 1 )[ 84 ]. DM induces and accelerates the development of atherosclerosis via multiple mechanisms that include metabolic derangements, smooth muscle dysfunction, oxidative stress, potentiated platelet function, increased coagulability, and chronic inflammation[ 85 ].…”
Section: Diabetes-associated Lower Extremity Complications and Their ...mentioning
confidence: 99%
“…The result may be an overt occlusion, sometimes acutely when a thrombus forms, or when increasingly stenotic vessels result in reduced perfusion[ 86 ]. Patients with co-existing severe PAD are also more likely to have CVI[ 84 ], which contributes to poor wound healing by increasing hydrostatic pressure in the lower extremity, thereby promoting wound exudation[ 87 ].…”
Section: Diabetes-associated Lower Extremity Complications and Their ...mentioning
Diabetic eye disease is strongly associated with the development of diabetic foot ulcers (DFUs). DFUs are a common and significant complication of diabetes mellitus (DM) that arise from a combination of micro- and macrovascular compromise. Hyperglycemia and associated metabolic dysfunction in DM lead to impaired wound healing, immune dysregulation, peripheral vascular disease, and diabetic neuropathy that predisposes the lower extremities to repetitive injury and progressive tissue damage that may ultimately necessitate amputation. Diabetic retinopathy (DR) is caused by cumulative damage to the retinal mic-rovasculature from hyperglycemia and other diabetes-associated factors. The severity of DR is closely associated with the development of DFUs and the need for lower extremity revascularization procedures and/or amputation. Like the lower extremity, the eye may also suffer end-organ damage from macrovascular compromise in the form of cranial neuropathies that impair its motility, cause optic neuropathy, or result in partial or complete blindness. Additionally, poor perfusion of the eye can cause ischemic retinopathy leading to the development of proliferative diabetic retinopathy or neovascular glaucoma, both serious, vision-threatening conditions. Finally, diabetic corneal ulcers and DFUs share many aspects of impaired wound healing resulting from neurovascular, sensory, and immunologic compromise. Notably, alterations in serum biomarkers, such as hemoglobin A1c, ceruloplasmin, creatinine, low-density lipoprotein, and high-density lipoprotein, are associated with both DR and DFUs. Monitoring these parameters can aid in prognosticating long-term outcomes and shed light on shared pathogenic mechanisms that lead to end-organ damage. The frequent co-occurrence of diabetic eye and foot problems mandate that patients affected by either condition undergo reciprocal comprehensive eye and foot evaluations in addition to optimizing diabetes management.
“…In addition, the calf muscle acts as a peripheral pump, supporting circulatory function through venous return, and impairment of calf muscle function is an independent risk factor for mortality [ 2 ]. Indeed, the Gutenberg Health Study demonstrated that CVD is an independent risk factor for cardiovascular disease [ 3 ]; however, the relationship may be under-recognised by physicians in clinical practice [ 1 , 4 ]. Fig.…”
Evidence suggests that chronic venous disease (CVD) may be a cardiovascular disorder, as patients with CVD are prone to developing arterial (atherosclerosis) and venous (thromboembolism) diseases. This may be partly explained by shared risk factors. Thus, patients with CVD or cardiovascular disease require careful history-taking and physical assessment to identify coexisting pathologies and risk factors. This article summarises a symposium at the XIX World Congress of the International Union of Phlebology held in Istanbul, Turkey, in September 2022. Common pathophysiological features of CVD and cardiovascular disease are endothelial injury, hypercoagulability and systemic inflammation. In CVD, inflammation primarily affects the microcirculation, with changes in capillary permeability, vein wall and valve remodelling and increase in oxidative stress. Once patients develop symptoms/signs of CVD, they tend to reduce their physical activity, which may contribute to increased risk of cardiovascular disease. Data show that the presence of CVD is associated with an increased risk of cardiovascular disease, including peripheral arterial disease and heart failure (HF), and the risk of adverse cardiovascular events increases with CVD severity. In addition, patients with cardiovascular disease, particularly those with HF, are at increased risk of venous thromboembolism (VTE) and should be assessed for VTE risk if they are hospitalised with cardiovascular disease. Therefore, CVD management must include a multi-specialty approach to assess risk factors associated with both the venous and arterial systems. Ideally, treatment should focus on the resolution of endothelial inflammation to control both CVD and cardiovascular disease. International guidelines recommend various conservative treatments, including venoactive drugs (VADs), to improve the symptoms/signs of CVD. Micronized purified flavonoid fraction (MPFF) is a VAD, with high-quality evidence supporting its use in relieving symptoms/signs of CVD and improving quality of life. Moreover, in large-scale observational studies, MPFF has shown superior effectiveness in real-world populations compared with other VADs.
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