Abstract 17179: Blunted Vasoreactivity and Loss of Flow Reserve Contribute to Impaired Arteriogenesis in Diabetic Peripheral Artery Disease

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
XinLu Wang ◽  
Michael Simons ◽  
William Sessa ◽  
Zhen W Zhuang
Keyword(s):  
Peripheral Artery Disease ◽  
Femoral Artery ◽  
Unmet Need ◽  
Diabetic Mice ◽  
Feeding Artery ◽  
Peripheral Artery ◽  
Flow Reserve ◽  
Collateral Arteries ◽  
Chronic Hyperglycemia ◽  
Artery Disease

Introduction: Given the uncertainty around the exact pathophysiological mechanisms of diabetic peripheral artery disease (PAD), patients continue to have extremely poor prognoses. Our study attempted to address this critical unmet need. Hypothesis: We hypothesize that vasoreactivity in the feeding artery and impaired peripheral flow reserve are two primary causes of impaired arteriogenesis in these patients. Methods: The distal right femoral artery was ligated 2 weeks after streptozocin (STZ, n=12) or citrate buffer (n=12) treatment in wild-type (WT) mice. The contralateral hindlimbs were used as a negative control. 2 weeks post-hindlimb ischemia (HLI), the endothelial (EC)-dependent and EC-independent vasodilatation of the feeding artery was investigated using a Vevo 770 preclinical ultrasound scanner. Peripheral flow reserve was also assessed by pulse wave Doppler after 60 ul adenosine (3mg/ml) was administered systemically. A microCT angiography was performed to quantify collateral arteries. Gastrocnemius muscles were taken both for immunohistochemical examination in the evaluation of angiogenesis. Results: Femoral diameters at rest were similar between both control and diabetic models. In the non-ischemic limb, diabetes markedly blunted endothelial and smooth muscle cell (SMC) vasodilation reaction in the proximal femoral artery when compared with control mice [[acetylcholine (Ach): 286.3 ±16 μm versus 370±30 μm; sodium nitroprusside (SNP): 285±24.5 μm versus 350±30 μm, p<0.01]. In the ischemic hindlimb, chronic ischemia impaired vasodilation in diabetic mice when compared with control mice (Ach: 255±16 μm versus 330±40 μm; SNP: 340±50 μm versus 253±22 μm, p<0.05). In diabetic mice, peripheral flow reserve was impaired (1.27±0.27 in controls vs 0.87±0.13 in diabetes, p<0.05), with arteriole rarefaction and increased capillary/muscle ratio. Conclusions: This study demonstrated that chronic hyperglycemia negatively affects collateral development at different levels: 1 ) dysregulation of the feeding artery; 2 ) impaired arteriogenesis and increased angiogenesis; and 3 ) loss of peripheral flow reserve.

Abstract 11: Effects of Canakinumab in Patients With Peripheral Artery Disease

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Kerry S Russell ◽  
Denise Yates ◽  
Andrea Feller ◽  
Tianke Wang ◽  
Ping Chen ◽  
...  
Keyword(s):  
Peripheral Artery Disease ◽  
Vascular Function ◽  
Cardiovascular Events ◽  
Ankle Brachial Index ◽  
Unmet Need ◽  
Walking Distance ◽  
Plaque Progression ◽  
Peripheral Artery ◽  
Plaque Volume ◽  
Artery Disease

Background: Peripheral artery disease (PAD) affects 8.5 million people in the US. PAD patients are at high risk for cardiovascular events, and their quality of life is often significantly impaired by decreased mobility. Interleukin-1β (IL-1β) may play an important role in this disease by promoting inflammatory responses that drive atherosclerotic plaque progression and impair vascular function. We sought to test whether interruption of IL-1β signaling would improve patient mobility and decrease plaque progression in the lower extremities. Methods: 38 patients (mean age 65; 71% male) with symptomatic PAD (confirmed by ankle-brachial index) were randomized 1:1 to receive Canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. Plaque volume in the superficial femoral artery (SFA) was assessed serially using 3.0T MRI. Mobility was assessed serially using the 6-minute walk test (maximum and pain-free walking distance). Results: Canakinumab was safe and well-tolerated. 12 patients discontinued (8 placebo, 4 Canakinumab). MRI data (from 31 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA at either time point in placebo-treated patients; nor was there a change in plaque volume in the Canakinumab-treated group. There was a serial and significant improvement in placebo-adjusted maximum and pain-free walking distance observed as early as 3 months after treatment with Canakinumab (58-meter improvement over placebo in pain-free distance at 3 months, P=0.01). Two placebo-treated patients required peripheral vascular interventions due to progression of disease; however, no Canakinumab-treated patients required revascularization during the study. Canakinumab decreased markers of systemic inflammation (IL-6 and hsCRP). Conclusions: Treatment with Canakinumab may improve maximum and pain-free walk distance in patients with symptomatic PAD. In conjunction with results soon to be reported for the CANTOS trial of Canakinumab for secondary prevention of cardiovascular events, additional studies may provide support that inhibition of IL-1β signaling can improve symptoms and function in this patient population with high unmet need.

Abstract 17377: Quantification of Arterial Stenosis Severity Based on the Changes in the Perfusion Wave Dynamics; a Novel Technology for Monitoring Peripheral Artery Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Tomer Heitner ◽  
Amit Livneh ◽  
Jonathan Lorber ◽  
Ron Karmeli ◽  
Amir Landesberg
Keyword(s):  
Early Detection ◽  
Peripheral Artery Disease ◽  
Unmet Need ◽  
The Elderly ◽  
Arterial Stenosis ◽  
Slow Phase ◽  
Peripheral Artery ◽  
Phase Duration ◽  
Stenosis Severity ◽  
Artery Disease

Introduction: Current screening modalities for peripheral artery disease (PAD) lack sensitivity especially in the elderly and diabetics, and there is an unmet need for early detection of restenosis after revascularization. Hypothesis: We have hypothesized that arterial stenosis is associated with adaptive arteriolar vasodilatation, which alters the downstream perfusion dynamics and prolongs the initial phase of the perfusion upstroke. These changes can be utilized for quantification of the arterial stenosis severity. Methods: We measured the lower leg perfusion with impedance plethysmography and compared it with other modalities used in the clinic and the gold-standard angiography. The various phases of the perfusion wave were identified by analyzing the first and second derivatives of the plethysmography. The signals were acquired from PAD patients before and after they underwent revascularization, to validate the ability to detect stenosis and successful revascularization. Results: Eighteen consenting patients were recruited (61±10 years old) and nineteen legs were treated. The perfusion upstroke encompasses 2 or 3 distinctive phases. An initial slow phase that is followed by a brisk upstroke and a final sallower augmentation in some patients. The slow phase duration (SPd) was 113±45 ms in extremities with above-knee (AK) arterial stenosis (n=17) while significantly shorter SPd of 26±0 ms was observed in limbs without AK stenoses (P = 0.011). In the AK extremities, the SPd significantly decreased to 52±40 ms after successful revascularization (P<0.01). Moreover, in AK cases with a satisfactory post-operative result (Duplex assessment), the SPd dramatically decreased from 103±35 ms before revascularization to 35±18 ms afterward (P<0.01, n=12). Conclusions: Analysis of the perfusion dynamic provides a gamut of precious indices. The SPd is a novel index that can detect and quantify the severity of arterial stenosis. The technology can significantly improve the surveillance of PAD patients and may be used for early detection of restenosis.

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.

Sensory neuron inositol-1,4,5-trisphosphate (IP3) receptors contribute to chronic mechanoreflex sensitization in rats with simulated peripheral artery disease

2021 ◽  
Author(s):  
Korynne S. Rollins ◽  
Alec L E Butenas ◽  
Auni C Williams ◽  
Steven W. Copp
Keyword(s):  
Skeletal Muscle ◽  
Receptor Antagonist ◽  
Sensory Neuron ◽  
Peripheral Artery Disease ◽  
Femoral Artery ◽  
Pressor Response ◽  
Peripheral Artery ◽  
Exercise Pressor Reflex ◽  
Pressor Reflex ◽  
Artery Disease

The mechanoreflex is exaggerated in patients with peripheral artery disease (PAD) and in a rat model of simulated PAD in which a femoral artery is chronically (~72hrs) ligated. We found recently that, in rats with a ligated femoral artery, blockade of thromboxane A2 (TxA2) receptors on the sensory endings of thin fiber muscle afferents reduced the pressor response to 1 Hz repetitive/dynamic hindlimb skeletal muscle stretch (a model of mechanoreflex activation isolated from contraction-induced metabolite production). Conversely, we found no effect of TxA2 receptor blockade in rats with freely perfused femoral arteries. Here we extended the isolated mechanoreflex findings in "ligated" rats to experiments evoking dynamic hindlimb skeletal muscle contractions. We also investigated the role played by inositol 1-4-5-trisphosphate (IP3) receptors, receptors associated with intracellular signaling linked to TxA2 receptors, in the exaggerated response to dynamic mechanoreflex and exercise pressor reflex activation in ligated rats. Injection of the TxA2 receptor antagonist daltroban into the arterial supply of the hindlimb reduced the pressor response to 1 Hz dynamic contraction in ligated but not "freely perfused" rats. Moreover, injection of the IP3 receptor antagonist xestospongin C into the arterial supply of the hindlimb reduced the pressor response to 1 Hz dynamic stretch and contraction in ligated but not freely perfused rats. These findings demonstrate that, in rats with a ligated femoral artery, sensory neuron TxA2 receptor and IP3 receptor mediated signaling contributes to a chronic sensitization of the mechanically activated channels associated with the mechanoreflex and the exercise pressor reflex.

scholarly journals Exaggerated cardiovascular responses to treadmill running in rats with peripheral arterial insufficiency

2018 ◽  
Vol 314 (1) ◽  
pp. H114-H121 ◽  
Author(s):  
J. Matthew Kuczmarski ◽  
Kellee Unrath ◽  
Gail D. Thomas
Keyword(s):  
Blood Flow ◽  
Peripheral Artery Disease ◽  
Femoral Artery ◽  
Muscle Blood Flow ◽  
Cardiovascular Responses ◽  
Treadmill Running ◽  
Female Rats ◽  
Peripheral Artery ◽  
Flow Capacity ◽  
Artery Disease

Patients with atherosclerotic peripheral artery disease have an augmented pressor response to treadmill walking, but the underlying mechanisms remain poorly understood and difficult to isolate because of the confounding presence of numerous cardiovascular risk factors. In the present study, we tested the hypothesis that a chronic deficit in muscle blood flow capacity would be sufficient to trigger an exaggerated pressor response to dynamic exercise. Sprague-Dawley rats (5 male and 5 female) were instrumented with radiotelemetry devices to measure the cardiovascular responses to treadmill running before and after bilateral femoral artery ligation, which has been previously shown to reduce the blood flow capacity of distal hindlimb muscles by >60%. Treadmill running evoked reproducible increases in mean arterial pressure (MAP) and heart rate (HR), which were significantly augmented 3 days after femoral artery ligation in both male rats [ΔMAP: +10 ± 1 (SE) vs. +18 ± 3 mmHg and ΔHR: +94 ± 12 vs. +148 ± 15 beats/min, P < 0.05] and female rats (ΔMAP: +16 ± 3 vs. +30 ± 5 mmHg and ΔHR: +128 ± 20 vs. +178 ± 19 beats/min, P < 0.05). Similar exaggerated MAP and HR responses were observed at repeated intervals between 3 and 65 days postligation. These findings indicate that a chronic deficit in muscle blood flow capacity is an important, persistent cause of the abnormal pressor and cardioaccelerator responses to dynamic exercise in both male and female rats with peripheral arterial insufficiency. NEW & NOTEWORTHY Using radiotelemetry to assess cardiovascular effects of exercise, we showed that femoral artery obstruction in male and female rats is an important, persistent cause of exaggerated pressor and cardioaccelerator responses to treadmill running. This translational model reproduces the abnormal cardiovascular response to exercise seen in patients with peripheral artery disease. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/treadmill-bp-in-simulated-peripheral-artery-disease/ .

Sign in / Sign up

Export Citation Format

Share Document