Abstract 115: Microvascular Response to Ramipril in Peripheral Artery Disease

Background: The myopathy of Peripheral Artery Disease (PAD), a consequence of ischemia caused by atherosclerotic plaques in arteries supplying the legs, is characterized by myofiber degeneration and fibrosis of the vascular walls and extramyofiber matrix. In association with fibrosis we have found a robust expression of the profibrotic cytokine TGFβ1 in vascular smooth muscle cells. Additionally, we have observed microvascular endothelial “swelling” in PAD muscle. Published data indicate that inhibitors of the angiotensin system reduce fibrosis in multiple organ systems and improve walking performance, in diverse patient populations. We hypothesize that “swelling” of microvasculature endothelial cells represents abnormal accumulation of basement membrane Collagen Type IV (Col-IV) and that treatment with Ramipril will improve the microvasculature. Methods and Results: Gastrocnemius biopsies of PAD patients at Fontaine Stage II (N=5) before and after six months of Ramipril intervention and control patients (N=4) were labeled with an antibody specific for Col-IV. Images were acquired with an automated wide-field microscope and then processed with Image Pro Plus® and AutoQuant® deconvolution software. We used Col IV label to measure wall thickness and lumen diameter of 230 to 360 microvessels per patient, with a custom MatLab program based on the Expectation Maximization algorithm coupled with a Gaussian Mixture Model. Microvessel wall thickness was significantly greater (p < 0.04) in PAD patients before (1.54 ± 0.04 μ) and after (1.61 ± 0.06 μ) Ramipril treatment compared to control (1.42 ± 0.02). Lumen diameter was significantly greater (p < 0.02) in Post-Ramipril (3.49 ± 0.04 μ) compared to Pre-Ramipril (3.18 ± 0.08 μ) and control (3.00 ± 0.11 μ) patients. Conclusions: The increase of microvessel lumen diameter with Ramipril treatment is expected to increase microvascular perfusion and thereby improve walking distance. Our study will be expanded to increase cohort size and evaluate the association of microvascular measurements with microperfusion determined by Contrast Enhanced Ultrasonography and with walking performance.

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Abstract 116: Revascularization but Not Supervised Exercise Therapy Prevents Progression of Fibrosis in the Gastrocnemius of Patients With Peripheral Artery Disease While Improving Limb Function

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.116 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Duy Ha ◽

George Casale ◽

Alicia Luis ◽

Kevin Harkins ◽

Reagan Huber ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Exercise Therapy ◽

Transforming Growth Factor ◽

Walking Distance ◽

Peripheral Artery ◽

Limb Function ◽

Supervised Exercise ◽

Walking Performance ◽

Artery Disease ◽

Tgf Β1

Introduction: Patients with peripheral artery disease (PAD) develop myofiber degeneration and fibrosis in their ischemic lower extremities, along with limb dysfunction. Walking performance improves with revascularization and exercise therapy, but effects on the myopathy are unknown. We previously showed fibrosis progresses with PAD and positively correlates with expression of vascular transforming growth factor-beta 1 (TGF-β1), a cytokine that stimulates collagen deposition. Hypothesis: We hypothesize that revascularization (RVS) and supervised exercise therapy (EXE) improve limb function in association with improved TGF-β1 dependent fibrosis. Methods: Gastrocnemius biopsies were collected from PAD patients (Fontaine Stage II; N=56) at baseline and 6 months after RVS (N=20), EXE (N=19), or no intervention (CTL; N=17). TGF-β1 expression was measured as grey scale units (gsu) by quantitative fluorescence microscopy of paraffin-embedded gastrocnemius sections. Collagen abundance was measured as optical density by quantitative multi-spectral bright-field microscopy of Masson Trichrome stained paraffin sections. Six Minute Walking Distance (SMWD), in meters, and Peak Walking Time (PWT), in seconds, were determined at baseline and 6 months. Relationships among TGF-β1, collagen, and limb function were assessed. Results: TGF-β1 expression and collagen density increased in CTL and EXE but not RVS patients. SMWD and PWT increased among RVS patients. PWT but not SMWD increased among EXE patients. SMWD and PWT were unchanged among CTL patients. The data are summarized in Table 1. Conclusions: RVS and EXE improved walking performance of patients with PAD, but only RVS prevented progression of fibrosis in the gastrocnemius of these patients. Over the same 6-month period, fibrosis increased in CTL muscle but was not sufficient to alter walking performance. The data suggest that benefits to the PAD leg may be greater with RVS compared to EXE.

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Multimodal Supervised Exercise Training is Effective in Improving Long Term Walking Performance in Patients with Symptomatic Lower Extremity Peripheral Artery Disease

Journal of Clinical Medicine ◽

10.3390/jcm10102057 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2057

Author(s):

Barbara Ney ◽

Stefano Lanzi ◽

Luca Calanca ◽

Lucia Mazzolai

Keyword(s):

Exercise Training ◽

Lower Extremity ◽

Peripheral Artery Disease ◽

Walking Distance ◽

Peripheral Artery ◽

Supervised Exercise ◽

Walking Performance ◽

Artery Disease ◽

Fontaine Stage

This study aimed to evaluate the effect of a multimodal supervised exercise training (SET) program on walking performance for 12 months in patients with symptomatic lower extremity peripheral artery disease (PAD). Consecutive patients with Fontaine stage II PAD participating in the SET program of our hospital were retrospectively investigated. Walking performance, assessed using a treadmill with measures of the pain-free and maximal walking distance (PFWD, MWD, respectively), and 6 min walking distance (6MWD), were tested before and following SET, as well as at 6 and 12 months after SET completion. Ninety-three symptomatic patients with PAD (65.0 ± 1.1 y) were included in the study. Following SET, the walking performance significantly improved (PFWD: +145%, p ≤ 0.001; MWD: +97%, p ≤ 0.001; 6MWD: +15%, p ≤ 0.001). At 6 months, PFWD (+257%, p ≤ 0.001), MWD (+132%, p ≤ 0.001), and 6MWD (+11%, p ≤ 0.001) remained significantly improved compared with the pre-SET condition. At 12 months, PFWD (+272%, p ≤ 0.001), MWD (+130%, p ≤ 0.001), and 6MWD (+11%, p ≤ 0.001) remained significantly improved compared with the pre-training condition. The walking performance remained significantly improved in both women and men for up to 12 months (p ≤ 0.001). Multimodal SET is effective at improving walking performance in symptomatic patients with PAD, with improvements lasting up to 12 months.

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Individual Differences in Response to Supervised Exercise Therapy for Peripheral Artery Disease

Western Journal of Nursing Research ◽

10.1177/0193945920977479 ◽

2020 ◽

pp. 019394592097747

Author(s):

Mary O. Whipple ◽

Erica N. Schorr ◽

Kristine M.C. Talley ◽

Julian Wolfson ◽

Ruth Lindquist ◽

...

Keyword(s):

Older Adults ◽

Peripheral Artery Disease ◽

Exercise Therapy ◽

Poor Response ◽

Walking Distance ◽

Peripheral Artery ◽

Meaningful Improvement ◽

Supervised Exercise ◽

Patient Reported ◽

Artery Disease

Nonresponse to exercise has been extensively examined in young athletes but is seldom reported in studies of aerobic exercise interventions in older adults. This study examined the prevalence of nonresponse and poor response to exercise in functional and quality of life outcomes and response patterns between and among older adults undergoing 12-weeks of supervised exercise therapy for the management of peripheral artery disease ( N = 44, mean age 72.3 years, 47.7% female). The prevalence of nonresponse (no change/decline in performance) in walking distance was 31.8%. The prevalence of poor response (lack of a clinically meaningful improvement) was 43.2%. Similar patterns of response were observed in both objective and patient-reported measures of physical function. All participants improved in at least one outcome; only two participants improved in all measured outcomes. Additional research should examine modifiable predictors of response to inform programming and maximize an individual’s potential benefit from exercise therapy.

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Development of an Exercise Training Protocol to Investigate Arteriogenesis in a Murine Model of Peripheral Artery Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20163956 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3956 ◽

Cited By ~ 4

Author(s):

Ayko Bresler ◽

Johanna Vogel ◽

Daniel Niederer ◽

Daphne Gray ◽

Thomas Schmitz-Rixen ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Suitable Model ◽

Peripheral Artery ◽

Running Wheel ◽

Limb Perfusion ◽

Collateral Growth ◽

Artery Disease ◽

Set Up ◽

Exercise Induced ◽

And Control

Exercise is a treatment option in peripheral artery disease (PAD) patients to improve their clinical trajectory, at least in part induced by collateral growth. The ligation of the femoral artery (FAL) in mice is an established model to induce arteriogenesis. We intended to develop an animal model to stimulate collateral growth in mice through exercise. The training intensity assessment consisted of comparing two different training regimens in C57BL/6 mice, a treadmill implementing forced exercise and a free-to-access voluntary running wheel. The mice in the latter group covered a much greater distance than the former pre- and postoperatively. C57BL/6 mice and hypercholesterolemic ApoE-deficient (ApoE−/−) mice were subjected to FAL and had either access to a running wheel or were kept in motion-restricting cages (control) and hind limb perfusion was measured pre- and postoperatively at various times. Perfusion recovery in C57BL/6 mice was similar between the groups. In contrast, ApoE−/− mice showed significant differences between training and control 7 d postoperatively with a significant increase in pericollateral macrophages while the collateral diameter did not differ between training and control groups 21 d after surgery. ApoE−/− mice with running wheel training is a suitable model to simulate exercise induced collateral growth in PAD. This experimental set-up may provide a model for investigating molecular training effects.

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.11 ◽

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.

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Effect of a Home-Based Exercise Intervention of Wearable Technology and Telephone Coaching on Walking Performance in Peripheral Artery Disease

JAMA ◽

10.1001/jama.2018.3275 ◽

2018 ◽

Vol 319 (16) ◽

pp. 1665 ◽

Cited By ~ 54

Author(s):

Mary M. McDermott ◽

Bonnie Spring ◽

Jeffrey S. Berger ◽

Diane Treat-Jacobson ◽

Michael S. Conte ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Exercise Intervention ◽

Wearable Technology ◽

Peripheral Artery ◽

Home Based ◽

Walking Performance ◽

Artery Disease ◽

Telephone Coaching

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Leg heat therapy improves perceived physical function but does not enhance walking capacity or vascular function in patients with peripheral artery disease

Journal of Applied Physiology ◽

10.1152/japplphysiol.00277.2020 ◽

2020 ◽

Vol 129 (6) ◽

pp. 1279-1289

Author(s):

Jacob C. Monroe ◽

Chen Lin ◽

Susan M. Perkins ◽

Yan Han ◽

Brett J. Wong ◽

...

Keyword(s):

Physical Function ◽

Peripheral Artery Disease ◽

Vascular Function ◽

Controlled Study ◽

Peripheral Artery ◽

Walking Capacity ◽

Heat Therapy ◽

Walking Performance ◽

Artery Disease ◽

Potent Vasoconstrictor

This is the first sham-controlled study to investigate the effects of leg heat therapy (HT) on walking performance, vascular function, and quality of life in patients with peripheral artery disease (PAD). Adherence to HT was high, and the treatment was well tolerated. Our findings revealed that HT applied with water-circulating trousers evokes a clinically meaningful increase in perceived physical function and reduces the serum concentration of the potent vasoconstrictor endothelin-1 in patients with PAD.

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

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa144.p1234 ◽

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.

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